Substituted pyrrolizine compounds and uses thereof

ABSTRACT

This application relates generally to certain substituted pyrrolizine compounds, and pharmaceutical compositions which inhibit HBV replication, and methods of making and using them.

PRIORITY CLAIM

This application is a continuation of U.S. application Ser. No.17/089,030, filed Nov. 4, 2020, which is a divisional of U.S.application Ser. No. 16/403,247, filed May 3, 2019, which is adivisional of U.S. application Ser. No. 15/686,499, filed Aug. 25, 2017,which claims priority to U.S. Provisional Application Nos. 62/380,063,filed Aug. 26, 2016, and 62/416,020, filed Nov. 1, 2016, all of whichare incorporated herein in their entireties for all purposes.

FIELD

This application relates generally to certain substituted pyrrolizinecompounds, and pharmaceutical compositions which inhibit HBVreplication, and methods of making and using them.

BACKGROUND

The hepatitis B virus (HBV) is an enveloped, partially double-strandedDNA virus. HBV is an infectious disease that affects the liver. Initialsymptoms of infection may include vomiting, jaundice, lethargy, darkurine, and abdominal pain. Chronic HBV infection can result in cirrhosisand liver cancer. Currently available therapies can inhibit replicationof the virus and minimize liver damage; however, there are no currentlyavailable therapies that can reliably clear an HBV infection.

In view of the continued prevalence of HBV infection, there is a needfor new therapeutic options, including new inhibitors of HBVreplication. Additionally, compounds capable of inhibiting HBVreplication while having low predicted metabolic clearance are ofparticular interest.

SUMMARY

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

-   -   R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A), C₃₋₈        cycloalkyl optionally substituted with 1 to 4 R^(1B), or 3 to 8        membered monocyclic or bicyclic heterocyclyl having 1 to 3        heteroatoms selected from N, O, and S, optionally substituted        with 1 to 3 R^(1C);        -   each R^(1A) is independently halogen, —OH, —CN, C₁₋₂            haloalkyl, —C(O)NR^(X)R^(Y), C₆₋₁₀ aryl optionally            substituted with 1 to 3 R^(1D), or a 5 to 8 membered            heteroaryl having 1 to 3 heteroatoms selected from N, O, and            S, optionally substituted with 1 to 3 R^(1D), provided no            more than 1 R^(1A) is C₆₋₁₀ aryl optionally substituted with            1 to 3 R^(1D) or 5 to 8 membered heteroaryl having 1 to 3            heteroatoms selected from N, O, and S optionally substituted            with 1 to 3 RID;        -   each R^(1B) is independently —CN, halogen, C₁₋₆ alkyl            optionally substituted with 1 to 3 —OH or —NR^(a)R^(b), C₂₋₄            alkynyl, C₁₋₄ alkoxy, C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl,            —C(O)NR^(X)R^(Y), or a 5 to 8 membered heteroaryl having 1            to 3 heteroatoms selected from N, O, and S optionally            substituted with 1 to 3 R^(1D), provided no more than 1            R^(1B) is C₃-6 cycloalkyl or 5 to 8 membered heteroaryl            having 1 to 3 heteroatoms selected from N, O, and S            optionally substituted with 1 to 3 R^(1D);        -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄            haloalkyl, —C(O)H, —C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl, or a 5            to 12 membered heteroaryl having 1 to 3 heteroatoms selected            from N, O, and S optionally substituted with 1 to 3 R^(1D),            provided no more than 1 R^(1C) is a 5 to 12 membered            heteroaryl having 1 to 3 heteroatoms selected from N, O, and            S optionally substituted with 1 to 3 R^(1D);        -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl            optionally substituted with 1 to 3 R^(Z), 3 to 8 membered            monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z);        -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally            substituted with 1 to 3 R^(Z).            -   or R^(X) and R^(Y) are taken together to form a 3 to 8                membered monocyclic or bicyclic heterocyclyl having 1 to                3 heteroatoms selected from N, O, and S, optionally                substituted with 1 to 3 R^(Z);            -   wherein each R^(Z) is independently halogen, methyl,                ethyl, oxo, —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered                monocyclic or bicyclic heterocyclyl having 1 to 3                heteroatoms selected from N, O, and S;        -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic            or bicyclic heterocyclyl having 1 to 3 heteroatoms selected            from N, O, and S, optionally substituted with 1 to 3 R^(Z);        -   each R^(b) is —H or C₁₋₃alkyl; or        -   R^(a) and R^(b) taken together form a 3 to 8 membered            monocyclic or bicyclic heterocycle optionally substituted            with 1 to 3 R^(Z);    -   the moiety

-   -    is a pyrrolidine or a 5-7 membered bicyclic heterocycle having        one nitrogen, optionally substituted with 1 to 6 R² groups;        -   wherein each R² is independently halogen, C₁₋₃alkyl, —OH, or            —OC₁₋₃ alkyl;    -   R³ is —H, halogen, or C₁₋₄ alkyl;    -   R⁴ is C₆₋₁₀ aryl optionally substituted with 1 to 5 R^(4A), or 5        to 12 membered heteroaryl having 1 to 3 heteroatoms selected        from N, O, and S, optionally substituted with 1 to 4 R^(4B); and    -   each R^(1D), R^(4A), and R^(4B) are independently —CN, halogen,        C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition comprises one or more additional therapeutic agents.

In certain embodiments, a method of inhibiting HBV replication isprovided, comprising administering a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, a method of treating or preventing a HBVinfection is provided, comprising administering to an individual (e.g. ahuman) in need thereof a therapeutically effective amount of a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof. In certain embodiments, the method of treating or preventing aHBV infection comprises administering one or more additional therapeuticagents.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in medical therapy isprovided.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for treating orpreventing a HBV infection, is provided.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a HBV infection, is provided.

Kits comprising the compounds, or pharmaceutically acceptable saltsthereof, or pharmaceutical compositions of the foregoing are alsoprovided. Articles of manufacture comprising a unit dose of thecompounds, or pharmaceutically acceptable salts thereof, of theforegoing are also provided. Methods of preparing compounds of thepresent disclosure are also provided.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

I. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience to indicate the point of attachment to a parent moiety;chemical groups may be depicted with or without one or more dasheswithout losing their ordinary meaning. A prefix such as “C_(u-v)” or(C_(u)-C_(v)) indicates that the following group has from u to v carbonatoms, where u and v are integers. For example, “C₁₋₆alkyl” indicatesthat the alkyl group has from 1 to 6 carbon atoms.

“Alkyl” is a linear or branched saturated monovalent hydrocarbon. Forexample, an alkyl group can have 1 to 10 carbon atoms (i.e.,(C₁₋₁₀)alkyl) or 1 to 8 carbon atoms (i.e., (C₁₋₈)alkyl) or 1 to 6carbon atoms (i.e., (C₁₋₆ alkyl) or 1 to 4 carbon atoms (i.e.,(C₁₋₄)alkyl). Examples of alkyl groups include, but are not limited to,methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkoxy” refers to the group —O-alkyl, where alkyl is as defined above.For example, C₁₋₄alkoxy refers to an —O-alkyl group having 1 to 4carbons.

“Alkynyl” is a linear or branched monovalent hydrocarbon radical with atleast one carbon-carbon triple bond. For example, an alkynyl group canhave 2 to 8 carbon atoms (i.e., C₂₋₈ alkyne,) or 2 to 6 carbon atoms(i.e., C₂₋₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).Examples of alkynyl groups include, but are not limited to, acetylenyl(—C≡CH), propargyl (—CH₂C≡CH), and —CH₂—C≡C—CH₃.

The term “halo” or “halogen” as used herein refers to fluoro (—F),chloro (—Cl), bromo (—Br) and iodo (—I).

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl areindependently replaced by a halo substituent, which may be the same ordifferent. For example, C₁₋₄haloalkyl is a C₁₋₄alkyl wherein one or moreof the hydrogen atoms of the C₁₋₄alkyl have been replaced by a halosubstituent. Examples of haloalkyl groups include but are not limited tofluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis also to be understood that when reference is made to a certainatom-range membered aryl (e.g., 6-10 membered aryl), the atom range isfor the total ring atoms of the aryl. For example, a 6-membered arylwould include phenyl and a 10-membered aryl would include naphthyl and1, 2, 3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groupsinclude, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (toform for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (toform for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form forexample indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isto be understood that the point of attachment for a heteroaryl orheteroaryl multiple condensed ring system can be at any suitable atom ofthe heteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). It also to beunderstood that when a reference is made to a certain atom-rangemembered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atomrange is for the total ring atoms of the heteroaryl and includes carbonatoms and heteroatoms. For example, a 5-membered heteroaryl wouldinclude a thiazolyl and a 10-membered heteroaryl would include aquinolinyl. Exemplary heteroaryls include but are not limited topyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, andtriazolyl.

The term “cycloalkyl” refers to a single saturated or partiallyunsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e.,C₃₋₂₀ cycloalkyl), for example from 3 to 12 annular atoms, for examplefrom 3 to 10 annular atoms. The term “cycloalkyl” also includes multiplecondensed, saturated and partially unsaturated all carbon ring systems(e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).Accordingly, cycloalkyl includes multicyclic carbocyles such as abicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 annular carbon atoms). Therings of a multiple condensed ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from oxygen,nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl grouphas from 5 to about 20 annular atoms, for example from 3 to 12 annularatoms, for example from 5 to 10 annular atoms. Thus, the term includessingle saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or7-membered rings) having from about 1 to 6 annular carbon atoms and fromabout 1 to 3 annular heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the ring. The rings of the multiplecondensed ring (e.g. bicyclic heterocyclyl) system can be connected toeach other via fused, spiro and bridged bonds when allowed by valencyrequirements. Heterocycles include, but are not limited to, azetidine,aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane,thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine,pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine,tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl,6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl,2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl,3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl,2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl,5-azaspiro[2.4]heptanyl, and the like.

The term “oxo” as used herein refers to ═O.

A “compound of the present disclosure” includes compounds disclosedherein, for example a compound of the present disclosure includescompounds of Formula (I), (II), (III), (IIIa), or (IV), including thecompounds of Examples 1 to 32. Also, compounds of Examples 1-49 areincluded. Further, compounds of Examples 1 to 152 are included.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition); andc) relieving the disease or condition, e.g., causing the regression ofclinical symptoms, ameliorating the disease state, delaying theprogression of the disease, increasing the quality of life, and/orprolonging survival.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, in certain embodiments, the term“preventing HBV infection” refers to administering to a subject who doesnot have a detectable HBV infection an anti-HBV therapeutic substance.It is understood that the subject for anti-HBV preventative therapy maybe an individual at risk of contracting the HBV virus. It is alsounderstood that prevention does not require a 100% success rate. In someinstances, prevention may be understood as a reduction of the risk ofinfection, but not a complete elimination the occurrence of aninfection.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s).

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease. The effectiveamount will vary depending on the compound, the disease, and itsseverity and the age, weight, etc., of the subject to be treated. Theeffective amount can include a range of amounts. As is understood in theart, an effective amount may be in one or more doses, i.e., a singledose or multiple doses may be required to achieve the desired treatmentendpoint. An effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable or beneficial result may be or isachieved. Suitable doses of any co-administered compounds may optionallybe lowered due to the combined action (e.g., additive or synergisticeffects) of the compounds.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

As used herein, “co-administration” includes administration of unitdosages of the compounds disclosed herein before or after administrationof unit dosages of one or more additional therapeutic agents, forexample, administration of the compound disclosed herein within seconds,minutes, or hours of the administration of one or more additionaltherapeutic agents. For example, in some embodiments, a unit dose of acompound of the present disclosure is administered first, followedwithin seconds or minutes by administration of a unit dose of one ormore additional therapeutic agents. Alternatively, in other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed by administration of a unit dose of a compound of thepresent disclosure within seconds or minutes. In some embodiments, aunit dose of a compound of the present disclosure is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of a compound of the presentdisclosure. Co-administration of a compound disclosed herein with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of a compound disclosed herein and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of each agent are present in the body of the patient.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The compounds of described herein may be prepared and/or formulated aspharmaceutically acceptable salts or when appropriate as a free base.Pharmaceutically acceptable salts are non-toxic salts of a free baseform of a compound that possesses the desired pharmacological activityof the free base. These salts may be derived from inorganic or organicacids or bases. For example, a compound that contains a basic nitrogenmay be prepared as a pharmaceutically acceptable salt by contacting thecompound with an inorganic or organic acid. Non-limiting examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington: The Science and Practice ofPharmacy, 21^(st) Edition, Lippincott Williams and Wilkins,Philadelphia, Pa., 2006.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein also include salts derived from an appropriate base,such as an alkali metal (for example, sodium, potassium), an alkalineearth metal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X isC₁-C₄ alkyl). Also included are base addition salts, such as sodium orpotassium salts.

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomers, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosedcompounds also include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. Substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds of Formula (I), can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centres of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereorerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any said compounds.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

A “prodrug” is a biologically inactive derivative of a drug that uponadministration to the human body is converted to the biologically activeparent drug according to some chemical or enzymatic pathway.

II. COMPOUNDS

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,wherein:

-   -   R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A), C₃₋₈        cycloalkyl optionally substituted with 1 to 4 R^(1B), or 3 to 8        membered monocyclic or bicyclic heterocyclyl having 1 to 3        heteroatoms selected from N, O, and S, optionally substituted        with 1 to 3 R^(1C).        -   each R^(1A) is independently halogen, —OH, —CN, C₁₋₂            haloalkyl, —C(O)NR^(X)R^(Y), C₆₋₁₀ aryl optionally            substituted with 1 to 3 R^(1D), or a 5 to 8 membered            heteroaryl having 1 to 3 heteroatoms selected from N, O, and            S, optionally substituted with 1 to 3 R^(1D), provided no            more than 1 R^(1A) is C₆₋₁₀ aryl optionally substituted with            1 to 3 R^(1D) or 5 to 8 membered heteroaryl having 1 to 3            heteroatoms selected from N, O, and S optionally substituted            with 1 to 3 R^(1D);        -   each R^(1B) is independently —CN, halogen, C₁₋₆ alkyl            optionally substituted with 1 to 3 —OH or —NR^(a)R^(b), C₂₋₄            alkynyl, C₁₋₄ alkoxy, C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl,            —C(O)NR^(X)R^(Y), or a 5 to 8 membered heteroaryl having 1            to 3 heteroatoms selected from N, O, and S optionally            substituted with 1 to 3 R^(1D), provided no more than 1            R^(1B) is C₃₋₆ cycloalkyl or 5 to 8 membered heteroaryl            having 1 to 3 heteroatoms selected from N, O, and S            optionally substituted with 1 to 3 R^(1D);        -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄            haloalkyl, —C(O)H, —C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl, or a 5            to 12 membered heteroaryl having 1 to 3 heteroatoms selected            from N, O, and S optionally substituted with 1 to 3 R^(1D),            provided no more than 1 R^(1C) is a 5 to 12 membered            heteroaryl having 1 to 3 heteroatoms selected from N, O, and            S optionally substituted with 1 to 3 R^(1D);        -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl            optionally substituted with 1 to 3 R^(Z), 3 to 8 membered            monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z);        -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally            substituted with 1 to 3 R^(Z)            -   or R^(X) and R^(Y) are taken together to form a 3 to 8                membered monocyclic or bicyclic heterocyclyl having 1 to                3 heteroatoms selected from N, O, and S, optionally                substituted with 1 to 3 R^(Z)            -   wherein each R^(Z) is independently halogen, methyl,                ethyl, oxo, —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered                monocyclic or bicyclic heterocyclyl having 1 to 3                heteroatoms selected from N, O, and S;        -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic            or bicyclic heterocyclyl having 1 to 3 heteroatoms selected            from N, O, and S, optionally substituted with 1 to 3 R^(Z);        -   each R^(b) is —H or C₁₋₃alkyl; or        -   R^(a) and R^(b) taken together form a 3 to 8 membered            monocyclic or bicyclic heterocycle optionally substituted            with 1 to 3 R^(Z);    -   the moiety

-   -    is a pyrrolidine or a 5-7 membered bicyclic heterocycle having        one nitrogen, optionally substituted with 1 to 6 R² groups;        -   wherein each R² is independently halogen, C₁₋₃alkyl, —OH, or            —OC₁₋₃ alkyl;    -   R³ is —H, halogen, or C₁₋₄ alkyl;    -   R⁴ is C₆₋₁₀ aryl optionally substituted with 1 to 5 R^(4A), or 5        to 12 membered heteroaryl having 1 to 3 heteroatoms selected        from N, O, and S, optionally substituted with 1 to 4 R^(4B); and    -   each R^(1D) R^(4A), and R^(4B) are independently —CN, halogen,        C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III), (IIIa)or (IV), R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) orpyridinyl optionally substituted with 1 to 4 R^(4B). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa) or (IV),R⁴ is phenyl optionally substituted with 1 to 3 R^(4A). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa) or (IV),R⁴ is pyridinyl, optionally substituted with 1 to 4 R^(4B). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa) or (IV),each R^(1D) R^(4A), and R^(4B) are independently —CN, halogen, C₁₋₄alkyl, or C₁₋₄ haloalkyl. In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa) or (IV), each R^(4A) is independentlyCl, F, —CF₃, —CHF₂, —CH₃, —OCF₃, —OCF₂H, or —CN. In certain embodimentsof a compound of Formula (I), (II), (III), (IIIa) or (IV), each R^(4A)is independently Cl, F, —CF₃, —CHF₂, —CH₃, or —CN. In certainembodiments of a compound of Formula (I), (II), (III), (IIIa) or (IV),each R^(4B) is independently Cl, F, —CF₃, —CHF₂, —CH₃, —OCF₃, —OCF₂H, or—CN. In certain embodiments of a compound of Formula (I), (II), (III),(IIIa) or (IV), each R^(4B) is independently Cl, F, —CF₃, —CHF₂, —CH₃,or —CN.

In certain embodiments of a compound of Formula (I), (II), (III), (IIIa)or (IV), R⁴ is pyridinyl, optionally substituted with 1 to 3 groupsselected from F, Cl, CF₃, and CHF₂. In certain embodiments of a compoundof Formula (I), (II), (III), (IIIa) or (IV), R⁴ is pyridin-4-yl,optionally substituted with 1 to 3 groups selected from F, Cl, CF₃, andCHF₂.

In certain embodiments of a compound of Formula (I) or (II), R³ is —Clor —CH₃. In certain embodiments of a compound of Formula (I) or (II), R³is —CH₃.

In certain embodiments of a compound of Formula (I), the moiety

each of which is optionally substituted with 1 to 6 R².

In certain embodiments of a compound of Formula (I), the moiety

each of which is optionally substituted with 1 to 6 R².

In certain embodiments of a compound of Formula (I), the moiety

each of which is optionally substituted with 1 to 6 R².

In certain embodiments of a compound of Formula (I), the moiety

which is optionally substituted with 1 to 6 R².

In certain embodiments of a compound of Formula (I), the moiety

which is optionally substituted with 1 to 6 R².

In certain embodiments of a compound of Formula (I), the moiety

which is optionally substituted with 1 to 6 R².

For the avoidance of doubt, when the moiety

is a pyrrolidine or a 5-7 membered bicyclic heterocycle having onenitrogen, the one nitrogen refers to the nitrogen depicted in thestructure

In certain embodiments of a compound of Formula (I), each R² isindependently C₁₋₃alkyl, —OH, or —OC₁₋₃ alkyl. In certain embodiments ofa compound of Formula (I), each R² is independently R² is —CH₃ or OH.

In certain embodiments of a compound of Formula (I), the compound is acompound of Formula (II)

In certain embodiments of a compound of Formula (I), is a compound ofFormula (II) wherein:

-   -   R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A), C₃₋₈        cycloalkyl optionally substituted with 1 to 4 R^(1B), or 3 to 8        membered monocyclic or bicyclic heterocyclyl having 1 to 3        heteroatoms selected from N, O, and S, optionally substituted        with 1 to 3 R^(1C);        -   each R^(1A) is independently halogen, —OH, —CN, C₁₋₂            haloalkyl, —C(O)NR^(X)R^(Y), C₆₋₁₀ aryl optionally            substituted with 1 to 3 R^(1D), or a 5 to 12 membered            heteroaryl having 1 to 3 heteroatoms selected from N, O, and            S, optionally substituted with 1 to 3 R^(1D), provided no            more than 1 R^(1A) is C₆₋₁₀ aryl optionally substituted with            1 to 3 R^(1D) or 5 to 12 membered heteroaryl having 1 to 3            heteroatoms selected from N, O, and S optionally substituted            with 1 to 3 R^(1D);        -   each R^(1B) is independently —CN, halogen, C₁₋₆ alkyl            optionally substituted with 1 to 3 —OH or —NR^(a)R^(b), C₁₋₄            alkoxy, C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl, —C(O)NR^(X)R^(Y),            or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms            selected from N, O, and S optionally substituted with 1 to 3            R^(1D), provided no more than 1 R^(1B) is C₃₋₆ cycloalkyl,            or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms            selected from N, O, and S optionally substituted with 1 to 3            R^(1D);        -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄            haloalkyl, —C(O)H, —C(O)C₁₋₄ alkyl or —C(O)OC₁₋₄ alkyl;        -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl            optionally substituted with 1 to 3 R^(Z), 3 to 8 membered            monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z);        -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally            substituted with 1 to 3 R^(Z)            -   or R^(X) and R^(Y) are taken together to form a 3 to 8                membered monocyclic or bicyclic heterocyclyl having 1 to                3 heteroatoms selected from N, O, and S, optionally                substituted with 1 to 3 R^(Z)            -   wherein each R^(Z) is independently halogen, methyl,                ethyl, oxo, —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered                monocyclic or bicyclic heterocyclyl having 1 to 3                heteroatoms selected from N, O, and S;        -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic            or bicyclic heterocyclyl having 1 to 3 heteroatoms selected            from N, O, and S, optionally substituted with 1 to 3 R^(Z);        -   each R^(b) is —H or C₁₋₃alkyl; or        -   R^(a) and R^(b) taken together form a 3 to 8 membered            heterocycle optionally substituted with 1 to 3 R^(Z)    -   each of R^(2A), R^(2B), R^(2C), R^(2D), R^(2E), and R^(2F) are        independently —H, halogen, C₁₋₃alkyl, —OH, or —OC₁₋₃ alkyl, or        R^(2C) or R^(2D) may be taken together with R^(2E) or R^(2F) to        form a cyclopropyl group;    -   R³ is halogen or methyl;    -   R⁴ is phenyl optionally substituted with 1 to 5 R^(4A), or        pyridinyl, optionally substituted with 1 to 4 R^(4B); and    -   each R^(1D), R^(4A), and R^(4B) are independently —CN, halogen,        C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (I) or (II), R¹ is C₁₋₆alkyl optionally substituted with 1 to 3 R^(1A), C₃₋₈ cycloalkyloptionally substituted with 1 to 4 R^(1B), or 3 to 8 membered monocyclicor bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O,and S, optionally substituted with 1 to 3 R^(1C);

-   -   each R^(1A) is independently halogen, —OH, —CN, C₁₋₂ haloalkyl,        —C(O)NR^(X)R^(Y), C₆₋₁₀ aryl optionally substituted with 1 to 3        R^(1D), or a 5 to 12 membered heteroaryl having 1 to 3        heteroatoms selected from N, O, and S, optionally substituted        with 1 to 3 R^(1D), provided no more than 1 R^(1A) is C₆₋₁₀ aryl        optionally substituted with 1 to 3 R^(1D) or 5 to 12 membered        heteroaryl having 1 to 3 heteroatoms selected from N, O, and S        optionally substituted with 1 to 3 R^(1D);    -   each R^(1B) is independently halogen, C₁₋₆ alkyl optionally        substituted with 1 to 3 —OH or —NR^(a)R^(b), C₁₋₄ alkoxy, C₁₋₂        haloalkyl, —C(O)NR^(X)R^(Y), or 5 to 8 membered heteroaryl        having 1 to 3 heteroatoms selected from N, O, and S optionally        substituted with 1 to 3 R^(1D), provided no more than 1 R^(1B)        is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected        from N, O, and S optionally substituted with 1 to 3 R^(1D);    -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄ haloalkyl,        —C(O)H, —C(O)C₁₋₄ alkyl or —C(O)OC₁₋₄ alkyl;    -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl        optionally substituted with 1 to 3 R^(Z), 3 to 8 membered        monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms        selected from N, O, and S, optionally substituted with 1 to 3        R^(Z);    -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally        substituted with 1 to 3 R^(Z);        -   or R^(X) and R^(Y) are taken together to form a 3 to 8            membered monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z)        -   wherein each R^(Z) is independently halogen, methyl, ethyl,            oxo, —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered monocyclic or            bicyclic heterocyclyl having 1 to 3 heteroatoms selected            from N, O, and S;    -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic or        bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N,        O, and S, optionally substituted with 1 to 3 R^(Z);    -   each R^(b) is —H or C₁₋₃alkyl; or    -   R^(a) and R^(b) taken together form a 3 to 8 membered monocyclic        or bicyclic heterocyclyl optionally substituted with 1 to 3        R^(Z);    -   each of R^(2A), R^(2B), R^(2C), R^(2D), R^(2E), and R^(2F) are        independently —H, halogen, C₁₋₃alkyl, —OH, or —OC₁₋₃ alkyl, or        R^(2C) or R^(2D) may be taken together with R^(2E) or R^(2F) to        form a cyclopropyl group;    -   R³ is halogen or methyl;    -   R⁴ is phenyl optionally substituted with 1 to 5 R^(4A), or        pyridinyl, optionally substituted with 1 to 4 R^(4B); and    -   each R^(1D), R^(4A), and R^(4B) are independently —CN, halogen,        C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (I) or (II), thecompound is a compound of Formula (III)

wherein R¹, R^(2A), R^(2B), and R⁴, are as defined herein for (I), (II),(III), (IIIa), or (IV), or any combination thereof.

In certain embodiments of a compound of Formula (I), (II), or (III), thecompound is a compound of Formula (IIIa)

wherein R¹, R^(2A), R^(2B), and R⁴, are as defined herein for Formula(I), (II), (III), (IIIa), or (IV), or any combination thereof.

In certain embodiments of a compound of Formula (I) or (II), thecompound is a compound of Formula (IV):

wherein R¹ and R⁴, are as defined herein for are as defined herein forFormula (I), (II), (III), (IIIa), or (IV), or any combination thereof.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3R^(1A), C₃₋₈ cycloalkyl optionally substituted with 1 to 4 R^(1B), or 3to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, optionally substituted with 1 to3 R^(1C)

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3R^(1A). In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is C₁₋₆ alkyl optionally substituted with 1to 3 C₁₋₂haloalkyl. In certain embodiments of a compound of Formula (I),(II), (III), (IIIa), or (IV), R¹ is methyl, ethyl, propyl, butyl, orpentyl, optionally substituted with 1 to 3 R^(1A). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),R¹ is ethyl or butyl optionally substituted with C₁₋₂haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is ethyl, propyl, or butyl optionally substitutedwith 1 to 3 R^(1A), wherein each R^(1A) is independently C₁₋₂haloalkyl,—OH, —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), or —C(O)N(C₁₋₃alkyl)₂.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is C₃₋₈ cycloalkyl optionally substituted with 1 to4 R^(1B). In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionallysubstituted with 1 to 3 R^(1B). In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa), or (IV), each R^(1B) is independentlyhalogen, C₁₋₃alkyl substituted with —NR^(a)R^(b), —C(O)NR^(X)R^(Y), or 5to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O,and S optionally substituted with 1 to 3 R^(1D). In certain embodimentsof a compound of Formula (I), (II), (III), (IIIa), or (IV), each R^(1B)is independently fluoro, —CH₂NR^(a)R^(b), triazolyl, thiadiazolyl, or—C(O)NR^(X)R^(Y). In certain embodiments of a compound of Formula (I),(II), (III), (IIIa), or (IV), each R^(1B) is independently fluoro,—CH₂NR^(a)R^(b), or —C(O)NR^(X)R^(Y). In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), one or two R^(1B)is independently halo and one R^(1B) is —C(O)NR^(X)R^(Y). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),wherein R^(a) is methyl or a 4 to 7 membered monocyclic or bicyclicheterocyclyl having 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with 1 to 3 R^(1Z), R^(b) is —H, or R^(a) andR^(b) are taken together to form a 4 to 7 membered monocyclic orbicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, andS optionally substituted with 1 to 3 R^(1Z), R^(X) is methyl or a 4 to 7membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S optionally substituted with 1 to 3 R^(1Z),R^(Y) is —H, or R^(X) and R^(Y) are taken together to form a 4 to 7membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S optionally substituted with 1 to 3 R^(1Z). Incertain embodiments of a compound of Formula (I), (II), (III), (IIIa),or (IV), 1 or 2 R^(1B) is optionally fluoro and one R^(1B) is—CH₂NR^(a)R^(b), where R^(a) is thietanyl substituted with 1 to 3 oxo ormethyl groups or 2-oxa-6-azaspiro[3.3]heptanyl and R^(b) is —H or R^(a)and R^(b) are taken together to form 2-oxa-6-azaspiro[3.3]heptanyl. Incertain embodiments of a compound of Formula (I), (II), (III), (IIIa),or (IV), 1 or 2 R^(1B) is optionally fluoro and one R^(1B) is—C(O)NR^(X)R^(Y) wherein R^(X) is methyl or thietanyl optionallysubstituted with 1 to 3 methyl or oxo groups, R^(Y) is —H, or R^(X) andR^(Y) are taken together to form 2-oxa-6-azaspiro[3.3]heptanyl,2-thia-6-azaspiro[3.3]heptan-6-yl, azetidinyl,2,6-diazaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, each ofwhich is optionally substituted with 1 to 3 groups that areindependently fluoro, oxo, methyl, or —S(O)₂CH₃.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is C₃₋₅ cycloalkyl optionally substituted with 1 to4 R^(1B), wherein each R^(B) is independently halogen, ethynyl, —CN,C₁₋₃alkyl substituted with —OH, or —NR^(a)R^(b), —C(O)NR^(X)R^(Y),phenyl optionally substituted with 1 to 3 R^(1D), or 5 to 8 memberedheteroaryl having 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with 1 to 3 R^(1D)

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl, bicyclo[1.1.1]pentanyl, cyclobutyloptionally substituted with 1 to 3 R^(1B) wherein each R^(1B) isindependently halogen, ethynyl, —CN, C₁₋₃alkyl substituted with —OH or—NR^(a)R^(b), —C(O)NR^(X)R^(Y), phenyl optionally substituted with 1 to3 R^(1D), or 5 membered heteroaryl having 1 to 3 heteroatoms selectedfrom N, O, and S optionally substituted with 1 to 3 R^(1D)

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 fluoro and one of tetrazolyl optionally substituted withC₁₋₃alkyl, oxadiazolyl optionally substituted with C₁₋₃alkyl, triazolyloptionally substituted with C₁₋₃alkyl, or thiadiazolyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is a 3 to 8 membered monocyclic or bicyclicheterocyclyl having 1 to 3 heteroatoms selected from N, O, and S,optionally substituted with 1 to 3 R^(1C). In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), R¹ is a 3 to 5membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected fromN, O, and S, optionally substituted with 1 to 3 R^(1C). In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),R¹ is oxetanyl or thietanyl optionally substituted with 1 to 3 R^(1C).In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), each R^(1C) is independently C₁₋₃alkyl, —CF₃, or oxo.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is:

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is

In certain embodiments of a compound of Formula (I), (II), or (III), thecompound is a compound of Formula (IIIa)

wherein:R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(A), C₃₋₈cycloalkyl optionally substituted with 1 to 4 R^(1B), or R¹ is a 3 to 8membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S, optionally substituted with 1 to 3 R^(1C);

-   -   each R^(1A) is independently C₁₋₂haloalkyl;    -   each R^(1B) is independently halogen, C₁₋₆ alkyl optionally        substituted with one NR^(a)R^(b), C₁₋₂ haloalkyl        —C(O)NR^(X)R^(Y), or 5 to 8 membered heteroaryl having 1 to 3        heteroatoms selected from N, O, and S optionally substituted        with 1 to 3 R^(1D) provided no more than 1 R^(1B) is C₃₋₆        cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3        heteroatoms selected from N, O, and S optionally substituted        with 1 to 3 R^(1D);        -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl            optionally substituted with 1 to 3 R^(Z), 3 to 8 membered            monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z);        -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally            substituted with 1 to 3 R^(Z)            -   or R^(X) and R^(Y) are taken together to form a 3 to 8                membered monocyclic or bicyclic heterocyclyl having 1 to                3 heteroatoms selected from N, O, and S, optionally                substituted with 1 to 3 R^(Z);    -   wherein each R^(Z) is independently halogen, methyl, ethyl, oxo,        —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered monocyclic or bicyclic        heterocyclyl having 1 to 3 heteroatoms selected from N, O, and        S;    -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄ haloalkyl;    -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic or        bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N,        O, and S, optionally substituted with 1 to 3 R^(Z);    -   each R^(b) is —H or C₁₋₃alkyl; or    -   R^(a) and R^(b) taken together form a 3 to 8 membered monocyclic        or bicyclic heterocycle optionally substituted with 1 to 3 R^(Z)    -   R^(2A) and R^(2B) are each —H;    -   R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) or        pyridinyl optionally substituted with 1 to 4 R^(4B), wherein        each R^(4A) is independently Cl, F, —CF₃, —CHF₂, —CH₃, —OCF₃,        —OCF₂H, or —CN and each R^(4B) is independently Cl, F, —CF₃,        —CHF₂, —CH₃, —OCF₃, —OCF₂H, or —CN; and        each R^(1D) is independently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄        haloalkyl.

In certain embodiments of a compound of Formula (III) or (IIIa), R¹ isC₃₋₈ cycloalkyl optionally substituted with 1 to 4 R^(1B), one or twoR^(1B) is optionally halogen and one R^(1B) is —C(O)NR^(X)R^(Y), R^(X)is C₁₋₆ alkyl, R^(Y) is —H, or R^(X) and R^(Y) are taken together toform a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, optionally substituted with 1 to3 R^(Z); wherein each R^(Z) is independently halogen, methyl, ethyl,oxo, —OH, —S(O)₂C₁₋₃alkyl, R^(2A) and R^(2B) are —H; R⁴ is phenyloptionally substituted with 1 to 5 R^(4A), or pyridinyl, optionallysubstituted with 1 to 4 R^(4B); and each R^(4A) and R^(4B) areindependently —CN, halogen, C₁₄ alkyl, or C₁₋₄ haloalkyl. In certainembodiments of a compound of Formula (III) or (IIIa), R¹ is C₃₋₈cycloalkyl optionally substituted with 1 to 4 R^(1B), one or two R^(1B)is optionally halogen and one R^(1B) is —C(O)NR^(X)R^(Y), R^(X) is C₁₋₆alkyl, R^(Y) is —H, or R^(X) and R^(Y) are taken together to form a 3 to8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S, optionally substituted with 1 to 3 R^(Z);wherein each R^(Z) is independently halogen, methyl, ethyl, oxo, —OH,—S(O)₂C₁₋₃alkyl, R^(2A) and R^(2B) are —H; R⁴ is phenyl optionallysubstituted with 1 to 5 R^(4A), or pyridinyl, optionally substitutedwith 1 to 4 R^(4B); and each R^(4A) and R^(4B) are independently —CN,halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (III) or (IIIa), R¹ iscyclobutyl optionally substituted with 1 to 3 R^(1B), one or two R^(1B)is optionally fluoro and one R^(1B) is —C(O)NR^(X)R^(Y), R^(X) is C₁₋₆alkyl, R^(Y) is —H, R^(2A) and R^(2B) are —H; R⁴ is phenyl optionallysubstituted with 1 to 5 R^(4A) which are independently Cl, F, —CF₃,—CHF₂, —CH₃, or —CN. In certain embodiments of a compound of Formula(III) or (IIIa), R¹ is cyclobutyl optionally substituted with 1 to 3R^(1B), one or two R^(1B) is optionally fluoro and one R^(1B) is—C(O)NR^(X)R^(Y), R^(X) is C₁₋₆ alkyl, R^(Y) is —H, R^(2A) and R^(2B)are —H; R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) which areindependently Cl, F, —CF₃, —CHF₂, —CH₃, —OCF₃, —OCF₂H, or —CN.

In certain embodiments of a compound of Formula (I) or (II), thecompound is a compound of Formula (IV):

wherein:

-   -   R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A), C₃₋₈        cycloalkyl optionally substituted with 1 to 4 R^(1B), or R¹ is a        3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to        3 heteroatoms selected from N, O, and S, optionally substituted        with 1 to 3 R^(1C);    -   each R^(1A) is independently C₁₋₂haloalkyl;    -   each R^(1B) is independently halogen, C₁₋₆ alkyl optionally        substituted with one NR^(a)R^(b), C₁₋₂ haloalkyl        —C(O)NR^(X)R^(Y), or 5 to 8 membered heteroaryl having 1 to 3        heteroatoms selected from N, O, and S optionally substituted        with 1 to 3 R^(1D) provided no more than 1 R^(1B) is 5 to 8        membered heteroaryl having 1 to 3 heteroatoms selected from N,        O, and S optionally substituted with 1 to 3 R^(1D);        -   each R^(X) is independently —H, C₃₋₆ cycloalkyl, C₁₋₆ alkyl            optionally substituted with 1 to 3 R^(Z), 3 to 8 membered            monocyclic or bicyclic heterocyclyl having 1 to 3            heteroatoms selected from N, O, and S, optionally            substituted with 1 to 3 R^(Z);        -   each R^(Y) is independently —H or C₁₋₆ alkyl optionally            substituted with 1 to 3 R^(Z)            -   or R^(X) and R^(Y) are taken together to form a 3 to 8                membered monocyclic or bicyclic heterocyclyl having 1 to                3 heteroatoms selected from N, O, and S, optionally                substituted with 1 to 3 R^(Z)    -   wherein each R^(Z) is independently halogen, methyl, ethyl, oxo,        —OH, —S(O)₂C₁₋₃alkyl, or 3 to 8 membered monocyclic or bicyclic        heterocyclyl having 1 to 3 heteroatoms selected from N, O, and        S;    -   each R^(1C) is independently C₁₋₆ alkyl, oxo, C₁₋₄ haloalkyl;    -   each R^(a) is —H, C₁₋₃alkyl, or a 3 to 8 membered monocyclic or        bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N,        O, and S, optionally substituted with 1 to 3 R^(Z);    -   each R^(b) is —H or C₁₋₃alkyl; or    -   R^(a) and R^(b) taken together form a 3 to 8 membered monocyclic        or bicyclic heterocycle optionally substituted with 1 to 3        R^(Z);    -   R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) or        pyridinyl optionally substituted with 1 to 4 R^(4B), wherein        each R^(4A) is independently Cl, F, —CF₃, —CHF₂, —CH₃, or —CN        and each R^(4B) is independently Cl, F, —CF₃, —CHF₂, —CH₃, or        —CN; and    -   each R^(1D) is independently —CN, halogen, C₁₄ alkyl, or C₁₋₄        haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III), (IIIa)or (VI), R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A),C₃₋₈ cycloalkyl optionally substituted with 1 to 4 R^(1B), or R¹ is a 3to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, optionally substituted with 1 to3 R^(1C); each R^(1A) is independently C₁₋₂haloalkyl; each R^(1B) isindependently halogen, C₁₋₆ alkyl optionally substituted with oneNR^(a)R^(b), —C(O)NR^(X)R^(Y), or 5 to 8 membered heteroaryl having 1 to3 heteroatoms selected from N, O, and S optionally substituted with 1 to3 R^(1D) provided no more than 1 R^(1B) is 5 to 8 membered heteroarylhaving 1 to 3 heteroatoms selected from N, O, and S; each R^(X) isindependently, C₁₋₆ alkyl optionally substituted with 1 to 3 R^(Z) or 3to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3heteroatoms selected from N, O, and S, optionally substituted with 1 to3 R^(Z); each R¹ is independently —H; or R^(X) and R¹ are taken togetherto form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1to 3 heteroatoms selected from N, O, and S, optionally substituted with1 to 3 R^(Z) wherein each R^(Z) is independently halogen, methyl, ethyl,oxo, —OH, or —S(O)₂C₁₋₃alkyl, each R^(1C) is independently C₁₋₆ alkyl,oxo, or C₁₋₄ haloalkyl; R^(a) and R^(b) taken together form a 3 to 8membered monocyclic or bicyclic heterocycle optionally substituted with1 to 3 R^(Z); R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) orpyridinyl optionally substituted with 1 to 4 R^(4B), and each R^(1D),R^(4A), and R^(4B) are independently —CN, halogen, C₁₋₄ alkyl,—OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III), (IIIa)or (VI), R¹ is C₁₋₄ alkyl optionally substituted with 1 to 3 R^(1A),cyclopropyl or cyclobutyl optionally substituted with 1 to 3 R^(1B), oroxetanyl or thietanyl optionally substituted with 1 to 3 R^(1C); eachR^(1A) is independently C₁₋₂haloalkyl; one or two R^(1B) is optionallyhalogen and one R^(1B) is C₁₋₃ alkyl optionally substituted with oneNR^(a)R^(b), —C(O)NR^(X)R^(Y), triazolyl optionally substituted with 1to 3 R^(1D) or thiadiazolyl optionally substituted with 1 to 3 R^(1D);each R^(X) is independently C₁₋₃ alkyl or thietanyl optionallysubstituted with 1 to 3 R^(Z); each R^(Y) is independently —H; or R^(X)and R^(Y) are taken together to form a 4 to 7 membered monocyclic orbicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, andS, optionally substituted with 1 to 3 R^(Z) wherein each R^(Z) isindependently halogen, methyl, ethyl, oxo, —OH, or —S(O)₂C₁₋₃alkyl, eachR^(1C) is independently C₁₋₃ alkyl, oxo, or C₁₋₃ haloalkyl; R^(a) andR^(b) taken together form a 3 to 8 membered monocyclic or bicyclicheterocycle optionally substituted with 1 to 3 R^(Z); R⁴ is phenyloptionally substituted with 1 to 5 —Cl, F, —CF₃, —CHF₂, —CH₃, or —CN;and each R^(1D) is independently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogen and —C(O)NR^(X)R^(Y) or —CH₂NR^(a)R^(b) whereinR^(X) and R^(Y) are taken together to form a 4 to 7 membered monocyclicor bicyclic heterocycle having 1 to 3 heteroatoms selected from N, O,and S optionally substituted with 1 to 3 R^(1Z) and R^(a) and R^(b) aretaken together to form a 4 to 7 membered monocyclic or bicyclicheterocycle having 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with 1 to 3 R^(1Z). In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), R^(X) and R^(Y)are taken together to for 2-oxa-6-azaspiro[3.3]heptanyl,2-thia-6-azaspiro[3.3]heptan-6-yl, azetidinyl,2,6-diazaspiro[3.3]heptanyl, or 6-oxa-1-azaspiro[3.3]heptan-1-yl each ofwhich is optionally substituted with 1 to 3 groups that areindependently fluoro, oxo, methyl, or —S(O)₂CH₃. In certain embodimentsof a compound of Formula (I), (II), (III), (IIIa), or (IV), R^(a) andR^(b) are taken together to form 2-oxa-6-azaspiro[3.3]heptanyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogens and a 5 to 8 membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S optionally substituted with 1 to 3R^(1D). In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionallysubstituted with 1 or 2 halogen and a 5 membered heteroaryl having 1 to3 heteroatoms selected from N, O, and S optionally substituted with 1 to3 R^(1D). In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionallysubstituted with 1 or 2 halogen and triazolyl or thiadiazolyl. Incertain embodiments of a compound of Formula (I), (II), (III), (IIIa),or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substituted with 1or 2 halogen and triazolyl. In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa), or (IV), R¹ is cyclopropyl orcyclobutyl, optionally substituted with 1 or 2 fluoro and triazolyl orthiadiazolyl. In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionallysubstituted with 1 or 2 fluoro and triazolyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogens and a 5 to 8 membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S optionally substituted with 1 to 3R^(1D); R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) orpyridinyl optionally substituted with 1 to 4 R^(4B), wherein each R^(4A)is independently —CN, halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, or C₁₋₄ haloalkyl and each R^(4B) is independently —CN,halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl,and each R^(1D) is independently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄haloalkyl. In certain embodiments of a compound of Formula (I), (II),(III), (IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionallysubstituted with 1 or 2 halogens and a 5 membered heteroaryl having 1 to3 heteroatoms selected from N, O, and S optionally substituted with 1 to3 R^(1D); R⁴ is phenyl optionally substituted with 1 to 3 R^(4A) whereineach R^(4A) is independently —CN, halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl,—OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl, and each R^(1D) is independently—CN, halogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), R¹ is cyclopropylor cyclobutyl, optionally substituted with 1 or 2 fluoro and atriazolyl; and R⁴ is phenyl optionally substituted with 1 to 3 R^(4A)wherein each R^(4A) is independently —CN, halogen, C₁₋₄ alkyl,—OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogens and a 5 to 8 membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S optionally substituted with 1 to 3R^(1D); R⁴ is phenyl optionally substituted with 1 to 5 R^(4A) orpyridinyl optionally substituted with 1 to 4 R^(4B), wherein each R^(4A)is independently Cl, F, —CF₃, —CHF₂, —CH₃, or —CN and each R^(4B) isindependently Cl, F, —CF₃, —CHF₂, —CH₃, or —CN; each R^(1D) isindependently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),R¹ is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2halogens and a 5 membered heteroaryl having 1 to 3 heteroatoms selectedfrom N, O, and S optionally substituted with 1 to 3 R^(1D); R⁴ is phenyloptionally substituted with 1 to 3 R^(4A) wherein each R^(4A) isindependently Cl, F, —CF₃, —CHF₂, —CH₃, or —CN and each R^(1D) isindependently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),R¹ is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2fluoro and a triazolyl; and R⁴ is phenyl optionally substituted with 1to 3 R^(4A) wherein each R^(4A) is independently Cl, F, —CF₃, —CHF₂,—CH₃, or —CN.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogens and a —C(O)NR^(X)R^(Y). In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), R¹ is cyclopropylor cyclobutyl, optionally substituted with 1 or 2 halogen and—C(O)NR^(X)R^(Y), wherein R^(X) is —H or C₁₋₆ alkyl optionallysubstituted with 1 to 3 R^(Z) and R^(Y) is —H or C₁₋₆ alkyl optionallysubstituted with 1 to 3 R^(Z). In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa), or (IV), R¹ is cyclopropyl orcyclobutyl, optionally substituted with 1 or 2 halogen and—C(O)NR^(X)R^(Y), wherein R^(X) is C₁₋₃ alkyl and R^(Y) is —H. Incertain embodiments of a compound of Formula (I), (II), (III), (IIIa),or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substituted with 1or 2 halogen and —C(O)NHCH₃. In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa), or (IV), R¹ is cyclobutyl substitutedwith 1 or 2 halogen and —C(O)NR^(X)R^(Y), wherein R^(X) is C₁₋₃ alkyland R¹ is —H.

In certain embodiments of a compound of Formula (I), (II), (III),(IIIa), or (IV), R¹ is cyclopropyl or cyclobutyl, optionally substitutedwith 1 or 2 halogens a —C(O)NR^(X)R^(Y); R⁴ is phenyl optionallysubstituted with 1 to 5 R^(4A) or pyridinyl optionally substituted with1 to 4 R^(4B), wherein each R^(4A) is independently —CN, halogen, C₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl and each R^(4B)is independently —CN, halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, or C₁₋₄ haloalkyl, and each R^(1D) is independently —CN,halogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. In certain embodiments of acompound of Formula (I), (II), (III), (IIIa), or (IV), R¹ is cyclopropylor cyclobutyl optionally substituted with 1 or 2 halogens and—C(O)NR^(X)R^(Y), wherein R^(X) is —H or C₁₋₆ alkyl optionallysubstituted with 1 to 3 R^(Z) and R^(Y) is —H or C₁₋₆ alkyl optionallysubstituted with 1 to 3 R^(Z); R⁴ is phenyl optionally substituted with1 to 3 R^(4A) wherein each R^(4A) is independently —CN, halogen, C₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₄ haloalkyl, or C₁₋₄ haloalkyl, and each R^(1D)is independently —CN, halogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. In certainembodiments of a compound of Formula (I), (II), (III), (IIIa), or (IV),R¹ is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2fluoro and —C(O)NR^(X)R^(Y), wherein R^(X) is C₁₋₃ alkyl and R¹ is —H;and R⁴ is phenyl optionally substituted with 1 to 3 R^(4A) wherein eachR^(4A) is independently —CN, halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, or C₁₋₄ haloalkyl. In certain embodiments of a compound ofFormula (I), (II), (III), (IIIa), or (IV), R¹ is cyclobutyl substitutedwith 1 or 2 fluoro and —C(O)NHCH₃ and R⁴ is phenyl optionallysubstituted with 1 to 3 R^(4A) wherein each R^(4A) is independently —CN,halogen, C₁₋₄ alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), or (IV), is

or a pharmaceutically acceptable salt thereof.

It is understood that each of the variables (e.g. R¹, R², R³, R⁴) may becombined with any other variables for Formula (I), (II), (III), (IIIa)or (IV) (e.g. R¹, R², R³, R⁴). That is, any of the values for R¹ may becombined with any other values for R², R³, R⁴, etc., described herein.

III. COMPOSITIONS

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure (e.g. acompound of Formula (I), (II), (II), (III), (IIIa), or (IV), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In certain embodiments, the pharmaceutical composition comprises one ormore additional therapeutic agent, as more fully set forth below.

Pharmaceutical compositions comprising the compounds disclosed herein,or pharmaceutically acceptable salts thereof, may be prepared with oneor more pharmaceutically acceptable excipients which may be selected inaccord with ordinary practice. Tablets may contain excipients includingglidants, fillers, binders and the like. Aqueous compositions may beprepared in sterile form, and when intended for delivery by other thanoral administration generally may be isotonic. All compositions mayoptionally contain excipients such as those set forth in the Rowe et al,Handbook of Pharmaceutical Excipients, 6^(th) edition, AmericanPharmacists Association, 2009. Excipients can include ascorbic acid andother antioxidants, chelating agents such as EDTA, carbohydrates such asdextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearicacid and the like. In certain embodiments, the composition is providedas a solid dosage form, including a solid oral dosage form.

The compositions include those suitable for various administrationroutes, including oral administration. The compositions may be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient (e.g., a compound of the presentdisclosure or a pharmaceutical salt thereof) with one or morepharmaceutically acceptable excipients. The compositions may be preparedby uniformly and intimately bringing into association the activeingredient with liquid excipients or finely divided solid excipients orboth, and then, if necessary, shaping the product. Techniques andformulations generally are found in Remington: The Science and Practiceof Pharmacy, 21^(st) Edition, Lippincott Williams and Wilkins,Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient. In one embodiment, thepharmaceutical composition is a tablet.

Pharmaceutical compositions disclosed herein comprise one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable excipient andoptionally other therapeutic agents. Pharmaceutical compositionscontaining the active ingredient may be in any form suitable for theintended method of administration. When used for oral use for example,tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, syrups or elixirsmay be prepared. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore excipients including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,lactose monohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutically acceptable excipient varies from about 5 to about 95%of the total compositions (weight:weight).

In certain embodiments, a composition comprising a compound of thepresent disclosure (e.g. a compound of Formula (I), (II), (II), (III),(IIIa), or (IV)), or a pharmaceutically acceptable salt thereof in onevariation does not contain an agent that affects the rate at which theactive ingredient is metabolized. Thus, it is understood thatcompositions comprising a compound of the present disclosure in oneaspect do not comprise an agent that would affect (e.g., slow, hinder orretard) the metabolism of a compound of the present disclosure or anyother active ingredient administered separately, sequentially orsimultaneously with a compound of the present disclosure. It is alsounderstood that any of the methods, kits, articles of manufacture andthe like detailed herein in one aspect do not comprise an agent thatwould affect (e.g., slow, hinder or retard) the metabolism of a compoundof the present disclosure or any other active ingredient administeredseparately, sequentially or simultaneously with a compound of thepresent disclosure.

IV. METHODS

In certain embodiments, the present disclosure provides methods fortreating a HBV infection, comprising administering to an individual(e.g. a human) infected with hepatitis B virus a therapeuticallyeffective amount a compound of the present disclosure or apharmaceutically acceptable salt thereof. Typically, the individual issuffering from a chronic hepatitis B infection, although it is withinthe scope of the present disclosure to treat people who are acutelyinfected with HBV.

In certain embodiments, a method of inhibiting HBV replication isprovided, comprising administering a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, the present disclosure provides a method forreducing the viral load associated with HBV infection infection, whereinthe method comprises administering to an individual (e.g. a human)infected with HBV a therapeutically effective amount of a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,wherein the therapeutically effective amount is sufficient to reduce theHBV viral load in the individual.

As described more fully herein, compounds of the present disclosure canbe administered with one or more additional therapeutic agent(s) to anindividual (e.g. a human) infected with HBV. The additional therapeuticagent(s) can be administered to the infected individual (e.g. a human)at the same time as a compound of the present disclosure or before orafter administration of a compound of the present disclosure.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in treating orpreventing a HBV infection is provided. In certain embodiments, acompound of the present disclosure (e.g. a compound of Formula (I)), ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a HBV infection is provided. Incertain embodiments, a compound of the present

As described more fully herein, compounds of the present disclosure canbe administered with one or more additional therapeutic agent(s) to anindividual (e.g. a human) infected with HBV. Further, in certainembodiments, when used to treat or prevent HBV, a compound of thepresent disclosure may be administered with one or more (e.g. one, two,three, four or more) additional therapeutic agent(s) selected from thegroup consisting of HBV combination drugs, HBV vaccines, HBV DNApolymerase inhibitors, immunomodulators toll-like receptor (TLR)modulators, interferon alpha receptor ligands, hyaluronidase inhibitors,hepatitis b surface antigen (HBsAg) inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilininhibitors, HBV viral entry inhibitors, antisense oligonucleotidetargeting viral mRNA, short interfering RNAs (siRNA) and ddRNAiendonuclease modulators, ribonucelotide reductase inhibitors, HBV Eantigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors,farnesoid X receptor agonists, HBV antibodies, CCR2 chemokineantagonists, thymosin agonists, cytokines, nucleoprotein modulators,retinoic acid-inducible gene 1 stimulators, NOD2 stimulators,phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1inhibitors, recombinant thymosin alpha-1, bruton's tyrosine kinase (BTK)inhibitors, KDM inhibitors, HBV replication inhibitors, arginaseinhibitors, and other HBV drugs.

V. ADMINISTRATION

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with for example thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure, may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In one variation, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In certain embodiments, the compound is administeredonce daily.

The compound can be administered by any useful route and means, such asby oral or parenteral (e.g., intravenous) administration.Therapeutically effective amounts of the compound may include from about0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day,such as from about 0.0001 mg/kg body weight per day to about 10 mg/kgbody weight per day, or such as from about 0.001 mg/kg body weight perday to about 1 mg/kg body weight per day, or such as from about 0.01mg/kg body weight per day to about 1 mg/kg body weight per day, or suchas from about 0.05 mg/kg body weight per day to about 0.5 mg/kg bodyweight per day, or such as from about 0.3 mg to about 30 mg per day, orsuch as from about 30 mg to about 300 mg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose.Other therapeutically effective amounts of the compound of the presentdisclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, or about 500 mg per dose. Othertherapeutically effective amounts of the compound of the presentdisclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225,250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dosecan be administered hourly, daily, or weekly. For example, a single dosecan be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or onceevery 24 hours. A single dose can also be administered once every 1 day,2, 3, 4, 5, 6, or once every 7 days. A single dose can also beadministered once every 1 week, 2, 3, or once every 4 weeks. In certainembodiments, a single dose can be administered once every week. A singledose can also be administered once every month.

Other therapeutically effective amounts of the compound of the presentdisclosure are about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, or about 100 mg per dose.

The frequency of dosage of the compound of the present disclosure arewill be determined by the needs of the individual patient and can be,for example, once per day or twice, or more times, per day.Administration of the compound continues for as long as necessary totreat the HBV infection. For example, a compound can be administered toa human being infected with HBV for a period of from 20 days to 180 daysor, for example, for a period of from 20 days to 90 days or, forexample, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

In one embodiment, pharmaceutical compositions comprising a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,in combination with one or more (e.g., one, two, three, four, one ortwo, one to three, or one to four) additional therapeutic agents, and apharmaceutically acceptable excipient are provided.

In one embodiment, kits comprising a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, in combination with oneor more (e.g., one, two, three, four, one or two, one to three, or oneto four) additional therapeutic agents are provided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In certain embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In certain embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In certain embodiments, a compound of the present disclosure isco-administered with one or more additional therapeutic agents.

VI. COMBINATION THERAPY

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HBV Combination Therapy

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV.

In certain embodiments, such tablets are suitable for once daily dosing.

In the above embodiments, the additional therapeutic agent may be ananti-HBV agent. For example, the additional therapeutic agent may beselected from the group consisting of HBV combination drugs, other drugsfor treating HBV, 3-dioxygenase (IDO) inhibitors, antisenseoligonucleotide targeting viral mRNA, Apolipoprotein A1 modulator,arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton'styrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist andmodulator, compounds targeting HBcAg, compounds targeting hepatitis Bcore antigen (HBcAg), covalently closed circular DNA (cccDNA)inhibitors, cyclophilin inhibitors, cytokines, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, gene modifiers or editors, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, HBV antibodies, HBV DNA polymeraseinhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBVvaccines, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B largeenvelope protein modulator, Hepatitis B large envelope proteinstimulator, Hepatitis B structural protein modulator, hepatitis Bsurface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg)secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,Immunoglobulin agonist, Immunoglobulin G modulator, immunomodulators,indoleamine-2, inhibitors of ribonucleotide reductase, Interferonagonist, Interferon alpha 1 ligand, Interferon alpha 2 ligand,Interferon alpha 5 ligand modulator, Interferon alpha ligand, Interferonalpha ligand modulator, interferon alpha receptor ligands, Interferonbeta ligand, Interferon ligand, Interferon receptor modulator,Interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors,histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killercell lectin-like receptor subfamily G member 1 inhibitors,lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptoractivators, microRNA (miRNA) gene therapy agents, modulators of Ax1,modulators of B7-H3, modulators of B7-H4, modulators of CD160,modulators of CD161, modulators of CD27, modulators of CD47, modulatorsof CD70, modulators of GITR, modulators of HEVEM, modulators of ICOS,modulators of Mer, modulators of NKG2A, modulators of NKG2D, modulatorsof OX40, modulators of SIRPalpha, modulators of TIGIT, modulators ofTim-4, modulators of Tyro, Na+-taurocholate cotransporting polypeptide(NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2gene stimulator, Nucleoprotein inhibitor, nucleoprotein modulators, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, Peptidylprolylisomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors,recombinant scavenger receptor A (SRA) proteins, recombinant thymosinalpha-1, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, short interfering RNAs (siRNA), short synthetic hairpin RNAs(sshRNAs), SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, gene modifiers or editors such as CRISPR (includingCRISPR Cas9) zinc finger nucleases or synthetic nucleases (TALENs), andcombinations thereof.

In certain embodiments, a compound of the present disclosure isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating HBV. In certain embodiments, the tabletcan contain another active ingredient for treating HBV, such as3-dioxygenase (IDO) inhibitors, Apolipoprotein A1 modulator, arginaseinhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosinekinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137 inhibitors,CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compoundstargeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg),core protein allosteric modulators, covalently closed circular DNA(cccDNA) inhibitors, cyclophilin inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, HBsAg inhibitors, HBsAg secretion or assemblyinhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors,HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors,Hepatitis B large envelope protein modulator, Hepatitis B large envelopeprotein stimulator, Hepatitis B structural protein modulator, hepatitisB surface antigen (HBsAg) inhibitors, hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotidereductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylaseinhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5inhibitors, killer cell lectin-like receptor subfamily G member 1inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin betareceptor activators, modulators of Ax1, modulators of B7-H3, modulatorsof B7-H4, modulators of CD160, modulators of CD161, modulators of CD27,modulators of CD47, modulators of CD70, modulators of GITR, modulatorsof HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A,modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,modulators of TIGIT, modulators of Tim-4, modulators of Tyro,Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, naturalkiller cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoproteininhibitor, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR9 gene stimulator, toll-like receptor (TLR)modulators, Viral ribonucleotide reductase inhibitors, and combinationsthereof.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from HBVcombination drugs, HBV vaccines, HBV DNA polymerase inhibitors,immunomodulators toll-like receptor (TLR) modulators, interferon alphareceptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen(HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1, bruton's tyrosine kinase(BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginaseinhibitors, and other HBV drugs.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NOV-205(molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-0061A,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US20150210682 (Roche), US2016/0122344 (Roche), WO2015173164, and WO2016023877.

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, andDTaP-rHB-Hib vaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), pradefovir, clevudine, ribavirin, lamivudine(EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754,FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate,tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymerpolyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785,RO-6871765, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod,resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051,SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and thecompounds disclosed in US20100143301 (Gilead Sciences), US20110098248(Gilead Sciences), and US20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), andUS20130251673 (Novira Therapeutics).

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A©), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON@, interferonalfa-n1(HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferonalfa-2b (Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon,interferon alfa-2b (Amega), interferon alfa-2b (Virchow),ropeginterferon alfa-2b, rHSA-IFN alpha-2a (recombinant human serumalbumin intereferon alpha 2a fusion protein), rHSA-IFN alpha 2b,recombinant human interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b(Amega), peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon,Urifron, interferon alfa-2b (Changchun Institute of BiologicalProducts), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, and Interapo(Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRX, IONIS-HBVRX, IONIS-GSK6-LRX, GSK-3389404.

Short Interfering RNAs (siRNA) and ddRNAi.

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBV E Antigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X Receptor Agonist

Example of farnesoid x receptor agonist such as EYP-001.

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies such as HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience)

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include AT-130, GLS4,NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate, JNJ-379, andDVR-23. Capsid assembly inhibitors such as AB-423.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen),WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira),US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira),US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira),US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350(Janssen), WO2013144129 (Roche).

Retinoic Acid-inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2, 3-dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte).

PD-1 Inhibitors

Examples of PD-1 inhibitors include nivolumab, pembrolizumab,pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226,STI-1110, and mDX-400.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), and GSK-2879552, RG-6016, ORY-2001.

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

HBV Combination Therapy

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, four, one or two,or one to three, or one to four) additional therapeutic agents and apharmaceutically acceptable excipient are provided.

HBV DNA Polymerase Inhibitor Combination Therapy

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor. In another specific embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with an HBV DNA polymerase inhibitor and at least oneadditional therapeutic agent selected from the group consisting of:immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, Arginase inhibitors, STINGagonists, PI3K inhibitors, lymphotoxin beta receptor activators, naturalkiller cell receptor 2B4 inhibitors, Lymphocyte-activation gene 3inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein4 (ipi4) inhibitors, CD137 inhibitors, Killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, epigenetic modifiers, modulators of NKG2D,modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CD161, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, IDO inhibitors, andhepatitis B virus replication inhibitors.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs©, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: immunomodulators, TLR modulators,HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs©, DUOBODIES®, BITES©, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2.

HBV Drug Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an additionaltherapeutic agent selected from the group consisting of adefovir(HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one or moreadditional therapeutic agents, wherein the one or more additionaltherapeutic agents is selected from tenofovir alafenamide, tenofoviralafenamide fumarate, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, and TCR-like antibodies),CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, IDO inhibitors, recombinantthymosin alpha-1, Arginase inhibitors, STING agonists, PI3K inhibitors,lymphotoxin beta receptor activators, natural killer cell receptor 2B4inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors,ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambd, BTK inhibitors,modulators of TIGIT, modulators of CD47, modulators of SIRPalpha,modulators of ICOS, modulators of CD27, modulators of CD70, modulatorsof OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4,modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulatorsof CD160, modulators of HEVEM, modulators of CD161, modulators of Ax1,modulators of Mer, modulators of Tyro, gene modifiers or editors such asCRISPR (including CRISPR Cas9), zinc finger nucleases or syntheticnucleases (TALENs), IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, andhepatitis B virus replication inhibitors.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®) or lamivudine (EPIVIR-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofpeginterferon alfa-2b (PEG-INTRON®), MULTIFERON®, interferon alpha 1b(HAPGEN®), interferon alpha-2b (INTRON A®), pegylated interferonalpha-2a (PEGASYS®), interferon alfa-n1 (HUMOFERON®), ribavirin,interferon beta-1a (AVONEX®), Bioferon, Ingaron, Inmutag (Inferon),Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon, and celmoleukin.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretionor assembly inhibitors, HBV therapeutic vaccines, HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus and bispecific antibodies and “antibody-like” therapeuticproteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fabderivatives, or TCR-like antibodies), cyclophilin inhibitors,stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I likereceptors, Arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1inhibitors, IDO inhibitors, and stimulators of NOD2.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one, two, or threeadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one or twoadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs©, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and one, two, three,or four additional therapeutic agents selected from the group consistingof immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors,HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBVantibodies including HBV antibodies targeting the surface antigens ofthe hepatitis B virus and bispecific antibodies and “antibody-like”therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs©,TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilininhibitors, stimulators of retinoic acid-inducible gene 1, stimulatorsof RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginaseinhibitors, PI3K inhibitors, IDO inhibitors, stimulators of NOD2 HBVviral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors,and nucleoprotein modulators (HBV core or capsid protein modulators).

In certain embodiments, a compound as disclosed herein (e.g., anycompound of Formula I) may be combined with one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents in any dosage amount of the compound of Formula I(e.g., from 10 mg to 1000 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 10 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide. A compound as disclosed herein(e.g., a compound of Formula I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 100-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300;150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400;350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 300 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 250 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 150 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Acompound as disclosed herein (e.g., a compound of Formula I) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, four, one or two, or one to three, or oneto four) additional therapeutic agents are provided.

VII. KITS

The present disclosure provides a kit comprising a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof. Thekit may further comprise instructions for use, e.g., for use in treatinga HBV infection. The instructions for use are generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable.

The present disclosure also provides a pharmaceutical kit comprising oneor more containers comprising a compound of the present disclosure or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice reflects approval by the agency for themanufacture, use or sale for human administration. Each component (ifthere is more than one component) can be packaged in separate containersor some components can be combined in one container wherecross-reactivity and shelf life permit. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

Also provided are articles of manufacture comprising a unit dosage of acompound of the present disclosure or a pharmaceutically acceptable saltthereof, in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

VIII. COMPOUND PREPARATION

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.)

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography. See, e.g.,Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin LayerChromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

The methods of the present invention generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordisatereomerically pure.

Representative syntheses of compounds of the present disclosure aredescribed in schemes below, and the particular examples that follow.

General Synthetic Schemes

Schemes 1-2 are provided as further embodiments of the invention andillustrate general methods which were used to prepare certain compoundsof the present disclosure and which can be used to prepare additionalcompounds of the present disclosure. Each of the variables (e.g. R¹, R²,R³, R⁴) can have the values as disclosed herein.

A1 can be converted to A2 by treatment with an appropriate alkyl halidesuch as (3-bromopropoxy)(tert-butyl)diphenylsilane in the presence of asuitable catalyst such as palladium dichloride bis(acetonitrile. A2 canbe converted to A3 through a deprotection with a suitable reagent suchas tetrabutylammonium fluoride and further halogenated to A4 with asuitable reagents such as carbon tetrabromide and triphenylphosphine.Cyclization to A5 can be effected with an appropriate radical initiatorsuch as 2,2′-azobis(2-methylpropionitrile) in the presence otherreagents such as tributyl tin hydride. Ester hydrolysis with a suitablereagent such as lithium hydroxide followed by amide formation viatreatment with an appropriate coupling reagent such as HATU and theappropriate aniline or by conversion to the acid chloride with a reagentsuch a thionyl chloride or oxalyl chloride followed by treatment withthe appropriate aniline gives A6. The aniline may be varied based on theR⁴ groups disclosed herein. Formation of A7 can be effected by treatmentwith a suitable reagent such as oxalyl chloride or ethyl2-chloro-2-oxoacetate and may or may not require the addition ofcatalyst such as aluminum chloride. Hydrolysis to A8 via a suitablereagent such as lithium hydroxide is followed by preparation of A9 bythe coupling of the appropriate amine such as1,1,1-trifluoropropan-2-amine in the presence of a coupling reagent suchas HATU. The amine may be varied for particular R¹ groups disclosedherein.

B1 can be converted to B2 by treatment with methyl2-chloro-2-oxoacetate. Conversion to B3 can be carried out with anappropriate hydroxide reagent such as lithium hydroxide or in some caseswith hydrogen gas and a suitable catalyst if the ester is a benzylester. B3 can be converted to B4 by treatment with a suitable reagentsuch as N,N′-diisopropylcarbodiimide and alkyne reagent B3B at elevatedtemperatures. Alternatively, B3 can be treated with oxalyl chloride,worked up and treated with B3B and a suitable base such as2,6-di-tert-butylpyridine to give B4. Hydrolysis to B5 can be effectedwith a suitable reagent such as lithium hydroxide. Conversion to B6occurs by addition of an appropriate amine (e.g. R¹—NH₂) and an amidecoupling reagent such as HATU. B6 can be converted to desired B7 bytreatment with a suitable reagent such as lithium hydroxide at elevatedtemperatures followed a second amide coupling with an appropriateaniline or heteroaryl amine (e.g R⁴—NH2) and a coupling reagent such asHATU. Alternatively, B5 can be treated with an aniline or heteroarylamine in the presence of a reagent such as Lithiumbis(trimethylsilyl)amide to give B6B followed by treatment with anappropriate amine and a coupling reagent such as HATU to give desiredB7.

REPRESENTATIVE EXAMPLES Example 1:7-(2-(tert-Butylamino)-2-oxoacetyl)-6-chloro-N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(1)

Step 1 A reaction tube with stirrer was charged with methyl3-chloro-1H-pyrrole-2-carboxylate (0.32 g, 2.0 mmol), norbornene (0.38g, 4.0 mmol), potassium bicarbonate (0.60 g, 6.0 mmol), palladium(II)dichloride bis(acetonitrile) (0.052 g, 0.2 mmol) and(3-bromopropoxy)(tert-butyl)diphenylsilane (1.51 g, 4 mmol) in anhydrousdimethylacetamide (2 mL) was heated at 90° C. for 24 h. Ethyl acetate(100 mL) was added and filtered. The filtrate was washed with water,brine and dried over sodium sulfate. Solvent was removed and the residuewas purified by column (0-80% Ethyl acetate in hexane) to give methyl1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-3-chloro-1H-pyrrole-2-carboxylate.

Step 2 To a solution of methyl1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-3-chloro-1H-pyrrole-2-carboxylate(0.72 g, 1.60 mmol) in tetrahydrofuran (10 mL) was added portion-wisetetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 1.6 mL, 1.6mmol) until completion of desilylation as judged by LC/MS. Solvent wasremoved and the residue was purified by silica gel chromatography (0-80%ethyl acetate in hexanes) to give methyl3-chloro-1-(3-hydroxypropyl)-1H-pyrrole-2-carboxylate: ¹H NMR (400 MHz,Chloroform-d) δ 6.80 (d, J=2.8 Hz, 1H), 6.17 (d, J=2.8 Hz, 1H), 4.42 (t,J=6.6 Hz, 2H), 3.88 (s, 3H), 3.61-3.49 (m, 2H), 2.02-1.92 (m, 2H).

Step 3 To a solution of methyl3-chloro-1-(3-hydroxypropyl)-1H-pyrrole-2-carboxylate (0.3 g, 1.4 mmol)and carbon tetrabromide (0.59 g, 1.79 mmol) in dichloromethane (5 mL)was added triphenylphosphine (0.54 g, 2 mmol) portionwise and themixture was stirred at ambient temperature for 30 min. The mixture waspurified by silica gel chromatography (0-80% ethyl acetate in hexanes)to give methyl 1-(3-bromopropyl)-3-chloro-1H-pyrrole-2-carboxylate: ¹HNMR (400 MHz, Chloroform-d) δ 6.85 (d, J=2.8 Hz, 1H), 6.16 (d, J=2.8 Hz,1H), 4.44 (t, J=6.4 Hz, 2H), 3.87 (s, 3H), 3.30 (dd, J=6.4, 5.8 Hz, 2H),2.33-2.20 (m, 2H).

Step 4 To mixture of methyl1-(3-bromopropyl)-3-chloro-1H-pyrrole-2-carboxylate (0.175 g, 0.624mmol), sodium cyanoborohydride (0.059 g, 0.94 mmol) in t-butanol (5 mL)were added tri-n-butyltinhydride (0.02 g, 0.06 mmol) and2,2′-azobis(2-methylpropionitrile) (0.051 g, 0.31 mmol) and the mixturewas stirred at reflux for 7 h. sodium cyanoborohydride and2,2′-azobis(2-methylpropionitrile) were added independently over houruntil HPLC indicated no starting material remained. Ethyl acetate (150mL) was added and the solution was washed with brine, dried over sodiumsulfate. Solvent was removed and the residue was purified by silica gelchromatography (0-80% ethyl acetate in hexanes) to give methyl6-chloro-2,3-dihydro-1H-pyrrolizine-5-carboxylate: ¹H NMR (400 MHz,Chloroform-d) δ 5.92 (t, J=0.8 Hz, 1H), 4.31-4.20 (m, 2H), 3.85 (s, 3H),2.84 (t, J=7.5 Hz, 2H), 2.44 (ddd, J=14.7, 8.0, 6.9 Hz, 2H).

Step 5 To a solution of methyl6-chloro-2,3-dihydro-1H-pyrrolizine-5-carboxylate (0.030 g, 0.18 mmol)in THF (2 mL), methanol (2 mL), and water (2 mL) added lithium hydroxidehydrate (0.076 g, 1.8 mmol) as solid and the solution was heated at 60°C. for 4 h then ambient temperature overnight. Organic solvent wasremoved by evaporation and ethyl acetate (50 mL) was added. The mixturewas acidified by addition of 1N HCl to pH=1. The organic layer wasseparated and dried over sodium sulfate. Solvent was removed to give6-chloro-2,3-dihydro-1H-pyrrolizine-5-carboxylic acid which was usedwithout purification.

To a mixture of 6-chloro-2,3-dihydro-1H-pyrrolizine-5-carboxylic acid(0.015 g, 0.081 mmol) in dichloromethane (5 mL) was added thionylchloride (0.2 mL) and the solution was heated at 70° C. for 3 h then 80°C. for 2 h. Solvent was removed and the residue was co-evaporated withtoluene twice. The residue was dissolved in dichloromethane (5 mL). Tothe solution was added triethylamine (3 eq) at 0° C. followed byaddition of aniline and 4-N,N-dimethylaminopyridine (20 mg). Thesolution was stirred at ambient temperature for 4 h. Ethyl acetate (100mL) was added and the solution was washed with water, brine and driedover sodium sulfate. Solvent was removed and the residue was purified bysilica gel chromatography (0-80% ethyl acetate in hexane) to give6-chloro-N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide:¹H NMR (400 MHz, Chloroform-d) β 8.58 (s, 1H), 8.05 (dd, J=5.5, 2.8 Hz,1H), 7.71 (ddd, J=9.1, 4.6, 2.8 Hz, 1H), 7.18 (dd, J=9.1, 8.3 Hz, 1H),5.97 (s, 1H), 4.40 (dd, J=7.9, 6.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.48(p, J=7.4 Hz, 2H).

Step 66-chloro-N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(5 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL) at 0° C. Tothe solution was added a solution (0.5 mL) of ethyl2-chloro-2-oxoacetate (0.5 mL) in dichloromethane (5 mL) drop-wise. Tothe solution was added aluminum chloride (20 mg, 0.18 mmol) at 0° C. andthe mixture was stirred at 0° C. for 45 min. Ethyl acetate (150 mL) wasadded and the aqueous layer was extracted with ethyl acetate (10 mL).The combined organic solution was washed with brine and dried oversodium sulfate. Solvent was removed and the residue was dissolved inethanol (5 mL). To the solution in ethyl acetate was added 2 N sodiumhydroxide (0.5 mL, 1 mmol) and the solution was stirred at 0° C. for 10min. Organic solvent was removed and the aqueous layer was mixed withethyl acetate (50 mL). The mixture was acidified by addition of 1Nhydrochloric acid to pH=1. The organic solution was washed with brineand dried over sodium sulfate. Solvent was removed to give2-(6-chloro-5-((3-chloro-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid which was used for the next reaction without further purification.

Step 7 To a solution of2-(6-chloro-5-((3-chloro-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (6 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) were addedt-butylamine (0.1 mL) and N,N-diisopropylethylamine (0.1 mL). To thesolution was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) portion-wise and the solution wasstirred at 0° C. for 10 min then at ambient temperature for 1 h. Solventwas concentrated to a small volume. Ethyl acetate (150 mL) was added andthe solution was washed with brine twice and dried over sodium sulfate.Solvent was removed and the residue was purified by silica gelchromatography (0-80% ethyl acetate in hexanes) to give7-(2-(tert-butylamino)-2-oxoacetyl)-6-chloro-N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(1).

Example 2:(R)—N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(2)

Step 1. To a solution of benzyl L-prolinate hydrochloride (8.83 g, 36.5mmol) and N-ethyldiisopropylamine (13 mL, 75 mmol) in dichloromethane(150 mL) chilled to 0° C. was added methyl chlorooxoacetate (5.0 mL, 54mmol) dropwise. The reaction mixture was warmed to ambient temperatureand stirred for 1 h, at which point the reaction mixture was quenched bypouring into a cooled aqueous solution of saturated sodium bicarbonate.The aqueous phase was thrice extracted to dichloromethane, the combinedorganic phases washed with brine, dried over sodium sulfate, filtered,and solvent removed under reduced pressure to provide benzyl(2-methoxy-2-oxoacetyl)-L-prolinate which was carried forward withoutfurther purification.

Step 2. A suspension of benzyl (2-methoxy-2-oxoacetyl)-L-prolinate (10.6g, 36.6 mmol) and 10 wt % palladium on carbon (˜50% water, 2.6 g, 1.2mmol) in ethanol (100 mL) was stirred under one atmosphere hydrogen for2 h. Upon completion of reaction the crude mixture was filtered throughcelite with ethanol rinses and concentrated under reduced pressure toprovide (2-methoxy-2-oxoacetyl)-L-proline which was carried forwardwithout further purification.

Step 3. A solution of (2-methoxy-2-oxoacetyl)-L-proline (0.64 g, 3.2mmol), ethyl 2-oxopent-3-ynoate (475 mg, 3.4 mmol), andN,N′-diisopropylcarbodiimide (0.55 mL, 3.6 mmol) inN-Methyl-2-pyrrolidone (6 mL) was stirred at 140° C. under microwaveheating for 45 minutes. The reaction mixture was then poured into asaturated aqueous solution of ammonium chloride and the aqueous phasethrice extracted to ethyl acetate. The combined organic phases weretwice washed with a 5% aqueous solution of lithium chloride followed bybrine, then dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by flash chromatographyon silica gel (0-50% ethyl acetate in hexanes) to provide methyl7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 4.30 (q, J=7.1 Hz, 2H), 4.26-4.18 (m,2H), 3.79 (s, 3H), 2.92 (t, J=7.6 Hz, 2H), 2.52 (s, 3H), 2.44 (p, J=7.6Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step 4. To a 0° C. chilled solution of7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(193 mg, 0.69 mmol) in ethanol (2 mL) was added a 4M aqueous solution ofsodium hydroxide (0.2 mL, 0.8 mmol). The reaction mixture was stirred at0° C. for 5 minutes and neutralized by the addition of dilute aqueoushydrogen chloride. The aqueous phase was thrice extracted to ethylacetate, dried over sodium sulfate, filtered, and concentrated underreduced pressure. One half of the solid obtained was dissolved inN-Methyl-2-pyrrolidone (2 mL) and treated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (160 mg, 0.42 mmol),R-trifluoroisopropylamine (0.04 mL, 0.4 mmol), andN-ethyldiisopropylamine (0.17 mL, 0.98 mmol) and stirred at ambienttemperature for 15 minutes. The reaction mixture was diluted with ethylacetate and washed sequentially with a 5% aqueous solution of lithiumchloride, a 5% aqueous solution of sodium bicarbonate, and brine. Theorganic phase was then dried over sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography on silicagel (0-20% ethyl acetate in hexanes) to provide methyl(R)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 7.06 (d, J=9.8 Hz, 1H), 4.74-4.59 (m,1H), 4.30 (t, J=7.4 Hz, 2H), 3.85 (s, 3H), 3.26 (dt, J=16.6, 7.9 Hz,1H), 3.20-3.08 (m, 1H), 2.60 (s, 3H), 2.46 (qd, J=7.8, 7.3, 3.0 Hz, 2H),1.41 (d, J=7.0 Hz, 3H)

Step 5. A solution of methyl(R)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxylate(58 mg, 0.17 mmol) in ethanol (2 mL) was treated with a 4M aqueoussolution of sodium hydroxide (0.4 mL, 1.6 mmol) and heated to 60° C. for2 h then neutralized by the addition of dilute aqueous hydrogenchloride. The aqueous phase was thrice extracted to ethyl acetate, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The solid obtained was dissolved in N-Methyl-2-pyrrolidone (1 mL) andtreated with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (88 mg, 0.23 mmol), 4-fluoro-3-chloroaniline(67 mg, 0.46 mmol), and N-ethyldiisopropylamine (0.08 mL, 0.43 mmol) andstirred at 80° C. for 2 h. The crude reaction mixture was passed througha syringe filtered and purified by preparative hplc (10-100%acetonitrile in water, 0.1% TFA buffer) to provide(R)—N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(2).

Synthesis of ethyl 2-oxopent-3-ynoate

Step 1. To a solution of ethyl glyoxylate (200 g, 1.96 mol, 1.0 eq) intoluene (1 L) at −40° C. was added a solution of propynylmagnesiumbromide (0.5 M in tetrahydrofuran, 4.28 L, 2.14 mol, 1.1 eq) dropwise.The reaction mixture was stirred at −40° C. for 1.5 h, and slowly warmedto 0° C. over 1 h. The reaction was monitored by TLC, quenched byaddition of saturated aqueous ammonium chloride solution (1 L). Theaqueous layer was extracted with ethyl acetate (2×1 L). The combinedorganic phases were washed with brine, dried over sodium sulfate,filtered, concentrated under reduced pressure. The residue was purifiedwith flash chromatography on silica (dichloromethane) to afford ethyl2-hydroxypent-3-ynoate: 1H NMR (400 MHz, CDCl3): δ 4.77 (q, J=2.4 Hz,1H), 4.35-4.24 (m, 2H), 1.85 (d, J=2.4 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H).

Step 2. To a solution of ethyl 2-hydroxypent-3-ynoate (90.0 g, 634 mmol,1.0 eq) in dichloromethane (250 mL) was added manganese dioxide (220 g,2.53 mol, 4.0 eq) was stirred for 5 h at ambient temperature. Thereaction mixture was filtered through a pad of Celite, and washed withdichloromethane, and concentrated under reduced pressure (careful toavoid loss of material due to product volatility). The residue waspurified with flash chromatography on silica gel (dichloromethane) toafford ethyl 2-oxopent-3-ynoate: 1H NMR (300 MHz, CDCl3): δ 4.35 (q,J=7.1 Hz, 2H), 2.15 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).

Example 3.N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(3)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(3) was synthesized in a manner similar to Example 2 using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of R-trifluoroisopropylamine.

Synthesis of 1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamidehydrochloride

Step 1. To a 0° C. solution of1-amino-3,3-difluorocyclobutane-1-carboxylic acid (990 mg, 6.55 mmol) inmethanol (8 mL) was added a 1M aqueous solution of sodium hydroxide (7mL, 7 mmol) followed by di-tert-butyl dicarbonate (1.8 g, 8.2 g). Thereaction mixture was warmed to ambient temperature was stirred for 14 h,acidified with dilute aqueous hydrogen chloride, and extracted todiethyl ether. The ethereal phase was washed with 1:1 water:brine, driedover sodium sulfate, filtered, and concentrated under reduced pressureto afford1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acidwhich was carried forward without further purification.

Step 2. To a 0° C. solution of1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid(1.65 g, 6.6 mmol), methanamine hydrochloride (2.28 g, 33.8 mmol), andtriethylamine (7.4 mL, 53 mmol) in N,N-dimethylformamide (24 mL) wasadded 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (3.75 g, 9.86 mmol). The reaction was warmedto ambient temperature and stirred for 20 h, at which point the reactionmixture was diluted with diethyl ether, washed with a saturate aqueoussolution of sodium bicarbonate, a 5% aqueous solution of lithiumchloride, and brine. The ethereal phase was then dried over sodiumsulfate, filtered, and concentrated under reduced pressure to affordtert-butyl (3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)carbamate whichwas carried forward without further purification.

Step 3. Tert-butyl (3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)carbamate(1.3 g, 4.92 mmol) was dissolved in a 4M solution of hydrogen chloridein dioxane (20 mL, 80 mmol) and stirred at 90° C. for 90 minutes.Solvent was removed under reduced pressure, twice azeotroping withtoluene, and the resultant material dried under high vacuum to afford1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride: ¹HNMR (400 MHz, DMSO-d6) δ 8.86 (s, 3H), 8.44 (s, 1H), 3.27 (dd, J=13.3,7.5 Hz, 2H), 3.05 (q, J=14.3 Hz, 2H), 2.69 (d, J=4.5 Hz, 3H).

Example 4 (1aS,6aS)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(4)

(1aS,6aS)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(4) was synthesized in a manner similar to Example 3 using benzyl(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxylate in place of benzylL-prolinate hydrochloride.

Example 5(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(5)

Step 1. A suspension of(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (500 mg, 2.20 mmol), 4-(dimethylamino)pyridine (592 mg, 4.85 mmol),and N,N′-dicyclohexylcarbodiimide (918 mg, 4.45 mmol) in dichloromethane(7 mL) was stirred at ambient temperature as benzyl alcohol (0.27 mL,2.61 mmol) was added. The resulting mixture was stirred at ambienttemperature overnight. The reaction mixture was diluted with diethylether (30 mL), and stirred at ambient temperature for 30 min beforefiltering off the solids. After the filtrate was concentrated, theresidue was dissolved in diethyl ether again and filtered off theinsoluble solids. (repeated 4 times) The residue was purified by silicagel column chromatography eluting 0-25% ethyl acetate in hexanes to give3-benzyl 2-(tert-butyl)(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate: ¹H NMR (400 MHz,Chloroform-d) δ 7.34 (m, 5H), 5.25-5.03 (m, 2H), 4.68 (dd, J=11.6, 3.0Hz, 0.4H), 4.55 (dd, J=11.5, 3.3 Hz, 0.6H), 3.55 (td, J=6.3, 2.5 Hz,0.6H), 3.46 (td, J=6.3, 2.4 Hz, 0.4H), 2.70-2.42 (m, 1H), 2.05 (q,J=2.8, 2.0 Hz, 0.6H), 2.01 (t, J=3.6 Hz, 0.4H), 1.45-1.55 (m, 1H), 1.49(s, 3.6H), 1.34 (s, 5.4H), 0.90 (td, J=5.5, 5.1, 2.4 Hz, 0.6H),0.87-0.80 (m, 0.4H), 0.77-0.69 (m, 0.6H), 0.65 (q, J=6.7 Hz, 0.4H):LCMS-ESI+ (m/z): [M-C₄H₈+H]⁺ calculated for C₁₄H₁₆NO₄: 262.11; found:261.81.

Step 2. A solution of 3-benzyl 2-(tert-butyl)(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (564 mg, 1.78mmol) in dichloromethane (2 mL) was stirred at ambient temperature astrifluoroacetic acid (2 mL) was added. After 1 h, the solution wasconcentrated and the residue was co-evaporated with toluene (×1) beforedrying in vacuum for 1 h to get crude benzyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate trifluoroacetic acidsalt: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₃H₁₆NO₂: 218.12; found:218.05.

A solution of the above crude benzyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride andN,N-diisopropylethylamine (0.78 mL, 4.48 mmol) in dichloromethane (5 mL)was stirred at 0° C. as methyl oxalyl chloride (0.18 mL, 1.96 mmol) wasadded. After 30 min at 0° C., the resulting solution was washed withwater. After the aqueous fraction was extracted with ethyl acetate, andthe combined organic fractions were dried over magnesium sulfate. Afterfiltration, solvent was removed and the residue was purified by silicagel column chromatography (0-85% ethyl acetate in hexanes) to givebenzyl(1R,5R)-2-(2-methoxy-2-oxoacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 7.44-7.28 (m, 5H), 5.34-5.28 (m, 0.5H),5.20-5.09 (m, 2H), 4.91 (dd, J=11.6, 3.3 Hz, 0.5H), 3.98-3.89 (m, 1H),3.91 (s, 1.5H), 3.69 (s, 1.5H), 2.77-2.65 (m, 0.5H), 2.65-2.53 (m,0.5H), 2.34 (dd, J=13.6, 2.6 Hz, 0.5H), 2.09 (dd, J=13.7, 3.3 Hz, 0.5H),1.72 (dq, J=8.9, 6.0 Hz, 0.5H), 1.61 (dq, J=8.7, 5.7 Hz, 0.5H), 1.01(ddd, J=6.4, 5.2, 2.6 Hz, 0.5H), 0.92-0.78 (m, 1H), 0.66-0.56 (m, 0.5H).LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₆H₁₈NO₅: 304.12; found: 304.01and 304.03.

Step 3. A mixture of benzyl(1R,5R)-2-(2-methoxy-2-oxoacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(504 mg, 1.66 mmol) and 20% palladium hydroxide on carbon (51 mg) inethanol (7 mL) was stirred under hydrogen atmosphere at room temperaturefor 45 min. The reaction mixture was filtered and the solids were washedwith ethanol. The filtrate was concentrated and co-evaporated withtoluene twice and dried in vacuo to give crude(1R,5R)-2-(2-methoxy-2-oxoacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₉H₁₂NO₅: 214.07; found:213.96.

To a solution of oxalyl chloride (2 mL, 7.11 mmol) and 1% DMF in toluene(1.8 mL) in toluene (10 mL) was added crude(1R,5R)-2-(2-methoxy-2-oxoacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2.32 mmol) in dichloromethane (4 mL) dropwise. The resultingsolution was stirred at ambient temperature for 1 h. The solution wasconcentrated and the residue was co-evaporated with toluene (10 mL). Theresulting residue was dried in vacuo for 30 min to give crude methyl2-((1R,5R)-3-(chlorocarbonyl)-214-azabicyclo[3.1.0]hexan-2-yl)-2-oxoacetate.

After the above crude methyl2-((1R,5R)-3-(chlorocarbonyl)-214-azabicyclo[3.1.0]hexan-2-yl)-2-oxoacetatewas dissolved in acetonitrile (4 mL), 2,6-di-tert-butylpyridine (0.57mL, 2.54 mmol) followed by ethyl 2-oxopent-3-ynoate (0.47 mL, 3.62 mmol)were added. The resulting solution was stirred at ambient temperaturefor 2 h. The mixture was concentrated and the residue was purified bysilica gel column chromatography eluting with 0-50% ethyl acetate inhexanes to give methyl(1aR,6aR)-5-(2-ethoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 4.43 (tt, J=6.0, 2.0 Hz, 1H), 4.36 (q,J=7.2 Hz, 2H), 3.89 (s, 3H), 3.23 (dd, J=18.4, 6.8 Hz, 1H), 3.12-2.99(m, 1H), 2.56 (s, 3H), 2.14-1.99 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.13(dt, J=8.7, 6.1 Hz, 1H), 0.35 (ddd, J=6.5, 5.1, 2.1 Hz, 1H): LCMS-ESI+(m/z): [M+H]⁺ calculated for C₁₅H₁₈NO₅: 292.12; found: 291.97.

Step 4. A solution of methyl(1aR,6aR)-5-(2-ethoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(322 mg, 1.11 mmol) was stirred in THF (3 mL), MeOH (3 mL) and water (3mL) and 1 N LiOH (2.2 mL) was added. After 1 h at ambient temperature,the reaction mixture was diluted with water and washed with ether (×1).The aqueous fraction was acidified with 1 N HCl, and the product wasextracted with ethyl acetate (×2). The combined extracts were dried withmagnesium sulfate and concentrated to give2-((1aR,6aR)-3-(methoxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid.

A solution of2-((1aR,6aR)-3-(methoxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid (279 mg, 1.06 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 605 mg, 1.59 mmol) and3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride(255 mg, 1.27 mmol) in DMF (3 mL) was stirred at ambient temperature asN,N-diisopropylethylamine (0.92 mL, 5.28 mmol) was added. After 30 minat rt, the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous ammonium chloride (×2), saturated aqueous sodiumbicarbonate (×2), and brine (×1). After the aq. fractions were extractedwith ethyl acetate (×1), the organic fractions were combined, dried overmagnesium sulfate. After filtration, solvent was removed and the residuewas purified by silica gel column chromatography eluting 0-100% ethylacetate in hexanes to give methyl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 1H), 6.66 (d, J=7.9 Hz, 1H),4.45 (tt, J=6.0, 2.0 Hz, 1H), 3.89 (s, 3H), 3.55-3.29 (m, 3H), 3.26-3.10(m, 1H), 3.00-2.83 (m, 2H), 2.82 (d, J=4.8 Hz, 3H), 2.56 (s, 3H),2.11-1.99 (m, 1H), 1.11 (dt, J=8.6, 6.0 Hz, 1H), 0.30 (ddd, J=6.1, 5.0,2.1 Hz, 1H): LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₂₂F₂N₃O₅:410.15; found: 410.01.

Step 5. To a solution of methyl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(212 mg, 0.52 mmol) in THF (2 mL), MeOH (2 mL) and water (3 mL) wasadded 1 N LiOH (1.6 mL) at rt. The resulting mixture was stirred at 60°C. bath for 8 h. After the reaction mixture was diluted with water andacidified with 1 N HCl, the product was extracted with ethyl acetate(6×). The combined extracts were dried with magnesium sulfate,concentrated, and dried to give crude(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid: LCMS-ESI+ (m/z): [M+H]+ calculated for C₁₈H₂₀F₂N₃O₅: 396.14;found: 396.01.

A solution of the above crude(1aR,6aR)-5-(2-((3,3-difluoro-1-methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 296 mg, 0.78 mmol) in dichloromethane(3 mL) was stirred at ambient temperature as N,N-diisopropylethylamine(0.36 mL, 2.07 mmol) was added. After 1.25 h at rt, the reaction mixturewas diluted with ethyl acetate (30 mL) and washed with saturated aqueousammonium chloride (×2), saturated aqueous sodium bicarbonate (×2), andbrine (×1). After the aq. fractions were extracted with ethyl acetate(×1), the organic fractions were combined, dried over magnesium sulfate.After filtration, solvent was removed and the residue was co-evaporatedwith toluene (×1) and dried in vacuum for 20 min give crude3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate.

Step 6. A solution of the above crude3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylateand 3-chloro-4-fluoroaniline (233 mg, 1.60 mmol) in2-methyltetrahydrofuran (5 mL) was stirred at ambient temperature as2,6-lutidine (0.24 mL, 2.06 mmol) was added. The resulting mixture wasstirred at 50° C. bath for 20 h followed by 75° C. for 70 h. Thereaction mixture was concentrated and the resulting residue was purifiedby silica gel column chromatography eluting 0-100% ethyl acetate inhexanes to give(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(5) and impure 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate.

Example 67-(2-((1-(1H-1,2,3-Triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(6)

Step 1. Methyl 3-methyl-1H-pyrrole-2-carboxylate (1000.0 mg, 7.186 mmol)in N,N-dimethylformamide (10 mL) was treated with potassiumhexamethyldisilazane (1M in tetrahydrofuran, 22 mL, 22 mmol) at −10° C.for 20 min. The reaction mixture was transferred into a solution of1,3-dibromopropane (14.51 g, 71.86 mmol) in N,N-dimethylformamide (5 mL)at −10° C. The reaction mixture was stirred for 90 min at the sametemperature. To the solution was added brine (30 mL) and the mixture wasextracted with ethyl acetate (30 mL×3). Combined organic layers werewashed with brine and dried over sodium sulfate. After filtration,solvent was removed and the residue was purified a silica gel columnchromatography (0-7% ethyl acetate/hexanes) to give methyl1-(3-bromopropyl)-3-methyl-1H-pyrrole-2-carboxylate LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₁₀H₁₅BrNO₂: 259.0; found: 259.1.

Step 2. Methyl 1-(3-bromopropyl)-3-methyl-1H-pyrrole-2-carboxylate (1450mg, 5.574 mmol) in toluene (364 mL) was treated withtri-n-butyltinhydride (3233.6 mg, 11.15 mmol) in the presence of1,1′-(diazene-1,2-diyl)bis(cyclohexane-1-carbonitrile) (408.6 mg, 1.672mmol, 0.3 equiv.) at 120° C. for 2 h. Toluene was removed under areduced pressure. To the residue was added aqueous 8% potassium fluoride(100 mL) and diethylether (100 mL) and stirred at ambient temperaturefor 10 h. After a filtration to remove colorless precipitation, themixture was extracted with diethylether. The organic layer was washedwith brine and dried over sodium sulfate. After a filtration, solventwas removed and the residue was purified by a silica gel chromatography(0-7% ethyl acetate/hexanes) to give methyl6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₁₀H₁₄NO₂: 180.1; found: 180.1.

Step 3. Methyl 6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate (165.0mg, 0.921 mmol) and 3-chloro-4-fluoroaniline (268.0 mg, 1.841 mmol) intetrahydrofuran (6 mL) was treated with lithium hexamethyldisilazane (1Min tetrahydrofuran, 2.76 mL, 2.76 mmol) at ambient temperature for 30min. To the reaction mixture was added water (30 mL) and the mixture wasextracted with ethyl acetate (3×30 mL). The organic layer was washedwith brine (30 mL) and dried over sodium sulfate. The solvent wasremoved under a reduced pressure and the crude mixture wasrecrystallized from ethyl acetate and hexanes repeatedly to giveN-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamideLCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₅H₁₅ClFN₂O: 293.1; found:293.1.

Step 4.N-(3-Chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(189.6 mg, 0.648 mmol) and methyl 2-chloro-2-oxoacetate (238.0 mg, 1.943mmol) in 1,2-dichloroethane (10 mL) was treated with aluminum chloride(431.8 mg, 3.238 mmol) and stirred at ambient temperature for 16 h.Celite (3 g), water (0.5 mL) and tetrahydrofuran (15 mL) were added andthe mixture was stirred at ambient temperature for 30 min. The mixturewas filtered through celite (3 g) using ethyl acetate (80 mL). Thesolvent was removed to give crude methyl2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetateLCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₁₇ClFN₂O₄: 379.1; found:379.1.

Step 5. Methyl2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate(245.5 mg, 0.648 mmol) was treated with aqueous 2N-lithium hydroxide (3mL) in tetrahydrofuran (3 mL) and methanol (6 mL) and stirred at ambienttemperature for 1 h. The reaction mixture was acidified with aqueous1N-hydrochloric acid (7 mL) at 0° C. The mixture was extracted withethyl acetate (3×30 mL). Combined organic layers were washed with brine(30 mL) and dried over sodium sulfate. The solvent was removed to givecrude2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₁₅ClFN₂O₄: 365.1; found:365.1.

Step 6.2-(5-((3-Chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (100.0 mg, 0.274 mmol) was treated with1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 312.7 mg, 0.822 mmol) in the presenceof N,N-diisopropylethylamine (212.6 mg, 1.645 mmol) in1,2-dichloroethane (2 mL) and stirred at ambient temperature for 10 min.The mixture was transferred into another flask charged with1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid (108.1mg, 0.548 mmol, 2 equiv.) in 1,2-dichloroethane (2 mL). The reactionmixture was stirred at ambient temperature for 30 min. To the mixturewas added water (30 mL) and the mixture was extracted with ethyl acetate(3×30 mL). Combined organic layers were washed with brine (30 mL) anddried over sodium sulfate. After a filtration, the organic solvent wasremoved under reduced pressure to give a crude mixture that was purifiedby preparative HPLC (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) to give7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(6).

Synthesis of 1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloricacid

Step 1 tert-Butyl (1-ethynylcyclopropyl)carbamate (200.0 mg, 1.104 mmol)was treated with azidotrimethylsilane (508.6 mg, 4.414 mmol, 4 equiv.)in the presence of copper iodide (21.0 mg, 0.11 mmol) inN,N-dimethylformamide (1 mL) and methanol (1 mL) and stirred at 110° C.for 2 h. After cooling, purification by prep HPLC (Phenomenex Luna C18column, 5% to 100% gradient acetonitrile in water with 0.1% TFA) gavetert-butyl (1-(1H-1,2,3-triazol-4-yl)cyclopropyl)carbamate. LCMS-ESI+(m/z): [M+H]⁺ calculated for C₁₀H₁₇N₄O₂: 225.1; found: 225.1.

Step 2 tert-Butyl (1-(1H-1,2,3-triazol-4-yl)cyclopropyl)carbamate (243.2mg, 1.084 mmol) was treated with hydrogen chloride (4N in 1,4-dioxane, 4mL) in methanol (2 mL) and stirred at 110° C. for 1 h. The organicsolvent was removed under a reduced pressure to give1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₅H₉N₄: 125.1; found: 125.1.

Example 7.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(7)

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(7) was synthesized in a manner similar to Example 2 using3-(trifluoromethyl)oxetan-3-amine in place of R-trifluoroisopropylamine.

Example 8N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(((3-methyl-1,1-dioxidothietan-3-yl)amino)methyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(8)

Step 1 To a suspension of 1-amino-3,3-difluorocyclobutane-1-carboxylicacid (300.0 mg, 1.99 mmol) and benzyl (2,5-dioxopyrrolidin-1-yl)carbonate (593.7 mg, 2.38 mmol, 1.2 equiv.) in acetonitrile (6 mL) atrt, was added diisopropylethylamine (796.8 mg, 5.96 mmol, 3 equiv.) andthe solution was stirred at the same temperature for 1 h. The reactionmixture was quenched with sat. sodium chloride aqueous solution (30 mL)and the whole was extracted with ethyl acetate (30 mL×3). Combinedorganic layer was washed with brine and dried over sodium sulfate. Afterfiltration, solvent was removed to give crude1-(((benzyloxy)carbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid(580 mg). This was used in the subsequent step without furtherpurification: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₃H₁₃F₂NNaO₄:308.1; found: 308.0.

Step 21-(((Benzyloxy)carbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid(566.2 mg, 1.985 mmol) and 3-amino-3-methylthietane 1,1-dioxide (268.3mg, 1.985 mmol, 1 equiv.) were treated with2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (2.80 g, 11.91 mmol, 6 equiv.) in the presence ofN,N-diisopropylethylamine (1.54 g, 11.91 mmol, 6 equiv.) indichloroethane at ambient temperature for 90 min. To the solution wasadded brine (30 mL) and the whole was extracted with ethyl acetate (30mL×3). Combined organic layer was washed with brine and dried oversodium sulfate. After filtration, solvent was removed and the residuewas purified by preparative reverse phase high performance liquidchromatography (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) to give benzyl(3,3-difluoro-1-((3-methyl-1,1-dioxidothietan-3-yl)carbamoyl)cyclobutyl)carbamate(356.4 mg). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₂₁F₂N₂O₅S: 403.1;found: 403.1.

Step 3 Benzyl(3,3-difluoro-1-((3-methyl-1,1-dioxidothietan-3-yl)carbamoyl)cyclobutyl)carbamate(218.8 mg, 0.54 mmol) was treated with 10% palladium carbon (210.0 mg)in methanol (10 mL) under a hydrogen atmosphere (1 atm) at ambienttemperature for 90 min. The mixture was filtered through Celite (3 g)using methanol (70 mL). Removal of the solvent from the filtrate under areduced pressure gave the1-amino-3,3-difluoro-N-(3-methyl-1,1-dioxidothietan-3-yl)cyclobutane-1-carboxamide.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₉H₁₅F₂N₂O₃S: 269.1; found:269.0.

Step 41-Amino-3,3-difluoro-N-(3-methyl-1,1-dioxidothietan-3-yl)cyclobutane-1-carboxamide(30.0 mg, 0.112 mmol) was treated with diisopropylalminum hydride (1M intetrahydrofuran, 0.6 mL, 0.60 mmol) at ambient temperature for 15 min.To the reaction mixture were added Celite (3 g), water (0.5 mL) andEtOAc (70 mL) to stir at ambient temperature for 30 min. The mixture wasfiltered through Celite (3 g) using EtOAc (30 mL). Removal of thesolvent gave the crude3-(((1-amino-3,3-difluorocyclobutyl)methyl)amino)-3-methylthietane1,1-dioxide (20.9 mg). LCMS-ESI+ (m/z): [M+H]⁺ calculated forC₉H₁₇F₂N₂O₂S: 255.1; found: 255.1.

Step 52-(5-((3-Chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (15.0 mg, 0.041 mmol) was treated with1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 93.8 mg, 0.247 mmol, 6 equiv.) in thepresence of diisopropylethylamine (31.9 mg, 0.247 mmol, 6 equiv.) in1,2-dichloroethane (2 mL) at ambient temperature for 20 min. The mixturewas transferred into another flask charged with3-(((1-amino-3,3-difluorocyclobutyl)methyl)amino)-3-methylthietane1,1-dioxide (20.9 mg, 0.082 mmol, 2 equiv.). The reaction mixture wasstirred at ambient temperature for 30 min. To the mixture was addedwater (30 mL) and the whole was extracted with ethyl acetate (30 mL×3).Combined organic layer was washed with brine (30 mL) and dried oversodium sulfate. After a filtration, the organic solvent was removedunder a reduced pressure to give a crude mixture. The crude mixture waspurified by a preparative reverse phase high performance liquidchromatography (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) to giveN-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(((3-methyl-1,1-dioxidothietan-3-yl)amino)methyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(8).

Example 9.N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-((3-methyl-1,1-dioxidothietan-3-yl)carbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-((3-methyl-1,1-dioxidothietan-3-yl)carbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(9) was synthesized in a manner similar to Example 2 using1-amino-3,3-difluoro-N-(3-methyl-1,1-dioxidothietan-3-yl)cyclobutane-1-carboxamidein place of 3,3-difluoro-1-(1H-1,2,3-triazol-5-yl)cyclobutan-1-amine.

Example 107-(2-((1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(10)

7-(2-((1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(10) was synthesized in a manner similar to Example 8 using2-oxa-6-azaspiro[3.3]heptane in step 2 in place of3-amino-3-methylthietane 1,1-dioxide.

Example 11N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(11)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(11) was synthesized in a manner similar to Example 8 and 9 using6-oxa-1-azaspiro[3.3]heptane in step 2 in place of3-amino-3-methylthietane 1,1-dioxide.

Example 127-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(12)

7-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(12) was synthesized in a manner similar to Example 6 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 13N-(3-chloro-4-fluorophenyl)-7-(2-((1-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptane-6-carbonyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(13)

N-(3-chloro-4-fluorophenyl)-7-(2-((1-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptane-6-carbonyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(13) was synthesized in a manner similar to Example 8 using2-thia-6-azaspiro[3.3]heptane 2,2-dioxide in place of3-amino-3-methylthietane 1,1-dioxide

Example 14N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(3-fluoroazetidine-1-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(14)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(3-fluoroazetidine-1-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(14) was synthesized in a manner similar to Example 8 using3-fluoroazetidine in place of 3-amino-3-methylthietane 1,1-dioxide

Example 15N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(15)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(15) was synthesized in a manner similar to Example 5 using benzyl(S)-5,5-dimethylpyrrolidine-2-carboxylate in place of benzyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate.

Example 16(R)—N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-2-hydroxy-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(16)

(R)—N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-2-hydroxy-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(16) was synthesized in a manner similar to Example 5 using benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate inplace of benzyl (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate.

Example 17(R)—N-(3-chloro-4-fluorophenyl)-3,3,6-trimethyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(17)

(R)—N-(3-chloro-4-fluorophenyl)-3,3,6-trimethyl-7-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(17) was synthesized in a manner similar to Example 5 using benzyl(S)-5,5-dimethylpyrrolidine-2-carboxylate in place of benzyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate andR-trifluoroisopropylamine in place of1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride.

Example 18N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(racemic) (18)

Example 22N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(single enantiomer) (22) Example 23N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(single enantiomer) (23)

RacecemicN-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (18) was synthesizedin a manner similar to Example 5 using benzyl(2S)-5-methylpyrrolidine-2-carboxylate in place of benzyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate. Single stereoisomerswere purified from racemic material via chiral supercritical fluidchromatography (OD-H column 4.6×100 mm, 3.0 ml/min, 30% isopropanol incarbon dioxide). The first eluting compound (0.85 min) was assigned thestructure of compound (22) and the second eluting compound (1.29 min)was assigned the structure of compound (23).

Example 19N-(3-cyano-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(19)

N-(3-cyano-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-3,6-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (19) was synthesizedin a manner similar to Example 5 using benzyl(2S)-5-methylpyrrolidine-2-carboxylate in place of benzyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate and3-cyano-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 20N-(3-chloro-4-fluorophenyl)-3,6-dimethyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(mixture

Example 24N-(3-chloro-4-fluorophenyl)-3,6-dimethyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(single diastereomer) (24) Example 25N-(3-chloro-4-fluorophenyl)-3,6-dimethyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(single diastereomer) (25)

A diastereomeric mixture ofN-(3-chloro-4-fluorophenyl)-3,6-dimethyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(20) was synthesized in a manner similar to Example 5 using benzyl(2S)-5-methylpyrrolidine-2-carboxylate in place of benzyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate andR-trifluoroisopropylamine in place of1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride.Single stereoisomers were purified from the mixture of diastereomers viachiral supercritical fluid chromatography (ID column, 4.6×150 mm, 3.0ml/min, 30% isopropanol in carbon dioxide). First peak 1.06 min 24,2^(nd) a peak 1.79 25

Example 21N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(21)

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(21) was synthesized in a manner similar to Example 6 using3-amino-3-methylthietane 1,1-dioxide in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 26N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-((3-methyl-1,1-dioxidothietan-3-yl)carbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(26)

Step 1 Methyl 6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate (52.1mg, 0.291 mmol) and 3,4,5-trifluoroaniline (85.5 mg, 0.581 mmol, 2equiv.) in tetrahydrofuran (6 mL) was treated with lithiumhexamethyldisilazane (1M in tetrahydrofuran, 0.87 mL, 0.87 mmol, 3equiv.) at ambient temperature for 30 min. To the reaction mixture wasadded water (30 mL) and the mixture was extracted with ethyl acetate (30mL×3). The organic layer was washed with brine (30 mL) and dried oversodium sulfate. The solvent was removed under a reduced pressure and thecrude mixture was purified by preparative reverse phase high performanceliquid chromatography (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) to give6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamideLCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₅H₁₄F₃N₂O: 295.1; found: 295.1.

Step 26-Methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(54.6 mg, 0.186 mmol) was treated with methyl 2-chloro-2-oxoacetate(68.2 mg, 0.557 mmol) in the presence of aluminum chloride (123.7 mg,0.928 mmol) in 1,2-dichloroethane (2 mL) at ambient temperature for 3.5h. To the reaction mixture were added Celite (3 g), water (0.5 mL),tetrahydrofuran (15 mL) and EtOAc (80 mL) and stirred at ambienttemperature for 30 min. The mixture was filtered through Celite (3 g)using ethyl acetate (30 mL×2). Removal of the solvent followed bypurification by preparative reverse phase high performance liquidchromatography (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) gave methyl2-(6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate:LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₁₆F₃N₂O₄: 381.1; found:381.1.

Step 3 Methyl2-(6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate(26.6 mg, 0.070 mmol) was treated with aqueous 2N-lithium hydroxide (1mL) in methanol (2 mL) and tetrahydrofuran (1 mL) at ambient temperaturefor 30 min. The mixture was acidified with 1N-hydrochloric acid (4 mL)under ice-water bath cooling. The mixture was extracted with ethylacetate (30 mL×2) and the combined organic layers were washed with brine(30 mL) and dried over sodium sulfate. After filtration, solvent wasremoved to give crude2-(6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₁₄F₃N₂O₄: 367.1; found:367.1.

Step 4 1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid(20.5 mg, 0.165 mmol, 2 equiv.) and2-(6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (30.2 mg, 0.082 mmol) was treated with2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (94.1 mg, 0.247 mmol) in the presence ofN,N-diisopropylethylamine (63.9 mg, 0.495 mmol) in 1,2-dichloroethane (2mL) and stirred for 16 h at ambient temperature. To the solution wasadded brine (30 mL) and the mixture was extracted with ethyl acetate (30mL×3). The combined organic layers were washed with brine (30 mL) anddried over sodium sulfate. After filtration, solvent was removed and theresidue was purified by preparative reverse phase high performanceliquid chromatography (Phenomenex Luna C18 column, 5% to 100% gradientacetonitrile in water with 0.1% TFA) to give7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(26).

Example 27N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(27)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(27) was synthesized in a manner similar to Example 8 using2-oxa-6-azaspiro[3.3]heptane in place of 3-amino-3-methylthietane1,1-dioxide.

Example 28N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(28)

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(28) was synthesized in a manner similar to Example 8 using2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane in place of3-amino-3-methylthietane 1,1-dioxide.

Example 29N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(29)

Step 1. Lithium bis(trimethylsilyl)amide solution (1.0 M intetrahydrofuran, 2.39 mL, 2.4 mmol) was added via syringe over 2 min toa stirred mixture of2-(5-(methoxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (150 mg, 0.597 mmol) and 3-chloro-4-fluoroaniline (400 mg, 2.39mmol) in tetrahydrofuran (5.0 mL) at 0° C. After 10 min, the reactionmixture was warmed to ambient temperature. After 19 h, saturated aqueousammonium chloride solution (10 mL) and diethyl ether (125 mL) were addedsequentially. The organic layer was washed sequentially with aqueoushydrogen chloride solution (0.5 M, 2×100 mL) and brine (50 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to give2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid.

Step 2.1-((Dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine3-oxide hexafluorophosphate(V) (391 mg, 1.03 mmol) was added as a solidto a stirred mixture of2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (150 mg, 0.411 mmol),3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminium chloride(95.3 mg, 0.452 mmol), and 4-methylmorpholine (226 μL, 2.06 mmol) inN,N-dimethylformamide (5.0 mL) at ambient temperature. After 17 h,piperidine (500 μL) was added. After 30 min, the reaction mixture waspurified by reverse phase preparative HPLC (10-100% acetonitrile inwater, 0.1% trifluoroacetic acid) to giveN-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(29).

Synthesis of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminiumchloride

Steps 1-3. Benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (696 mg, 2.79mmol) was added as a solid to a stirred mixture of3,3-difluoro-1-(hydroxymethyl)cyclobutan-1-aminium chloride (485 mg,2.79 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.22 mL, 6.99 mmol) indichloromethane (20 mL) at ambient temperature. After 19 h, water (5 mL)and diethyl ether (100 mL) were added sequentially. The organic layerwas washed with aqueous hydrogen chloride solution (2×70 mL) and water(70 mL), was dried over anhydrous magnesium sulfate, was filtered, andwas concentrated under reduced pressure. The residue was dissolved indichloromethane (20 mL), and the resulting solution was stirred atambient temperature. Dess-Martin periodinane (1.78 g, 4.19 mmol) wasadded as a solid. After 4 h, aqueous sodium thiosulfate solution (1.0 M,25 mL) and diethyl ether (100 mL) were added sequentially. The organiclayer was washed with saturated aqueous sodium bicarbonate solution(2×100 mL) and water (100 mL), was dried over anhydrous magnesiumsulfate, was filtered, and was concentrated under reduced pressure. Theresidue was dissolved in methanol (20 mL), potassium carbonate (1.16 g,8.38 mmol) was added as a solid, and the resulting heterogeneous mixturewas stirred at 0° C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (629 μL,4.19 mmol) was added via syringe. After 5 min, the reaction mixture waswarmed to ambient temperature. After 15 h, the reaction mixture wasfiltered through celite, and the filter cake was extracted with ethylacetate (80 mL). The filtrate was concentrated under reduced pressure,and the residue was dissolved in diethyl ether (100 mL). The organiclayer was washed with water (50 mL), was dried over anhydrous magnesiumsulfate, was filtered, and was concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (0 to10% ethyl acetate in hexanes) to give benzyl(1-ethynyl-3,3-difluorocyclobutyl)carbamate.

Step 4. Azidotrimethylsilane (344 μL, 2.59 mmol) was added via syringeto a stirred mixture of benzyl(1-ethynyl-3,3-difluorocyclobutyl)carbamate (491 mg, 1.85 mmol) andcopper(I) iodide (17.6 mg, 92.5 μmol) in N,N-dimethylformamide (3.5 mL)and methanol (0.4 mL) at ambient temperature, and the resulting mixturewas heated to 100° C. After 6 h, the reaction mixture was cooled toambient temperature, and diethyl ether (130 mL) was added. The organiclayer was washed sequentially with a mixture of brine and water (1:1v:v, 100 mL) and water (100 mL), was dried over anhydrous magnesiumsulfate, was filtered, and was concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (0 to40% ethyl acetate in hexanes) to give benzyl(3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)carbamate.

Step 5. A heterogeneous mixture of benzyl(3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)carbamate (307 mg,0.995 mmol) and palladium on activated carbon (10% wt/wt, 248 mg, 23.3μmol) in ethanol (10 mL) at ambient temperature was placed under 1 atmof hydrogen gas and stirred vigorously. After 1.5 h, the reactionmixture was filtered through celite, and the filter cake was extractedwith ethyl acetate (80 mL). Hydrogen chloride solution (4 M in1,4-dioxane, 0.5 mL) was added via syringe to the filtrate, and theresulting mixture was swirled vigorously for 1 min and then concentratedunder reduced pressure to give3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminium chloride.

Example 30(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(30)

Crude 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylatefrom Example 5 was purified by silica gel column chromatography elutingwith 0-10% methanol in dichloromethane. This material was converted todesired(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(30) in a manner similar to Example 5, Step 6 using5-amino-2-fluorobenzonitrile in place of 3-chloro-4-fluoroaniline.

Example 317-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(31)

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(31) was synthesized in a manner similar to Example 29 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 327-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(32)

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(32) was synthesized in a manner similar to Example 29 using4-fluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 33(1aS,6bR)-N-(3-chloro-4-fluorophenyl)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxamide(33)

Step 1. To benzyl alcohol (4.2 g, 39 mmol) was thionyl chloride (2.0 g,17.3 mmol) at 0° C. To this mixture was then added(1S,2R,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.5 g, 3.9mmol). The reaction was allowed to reach ambient temperature and stirredfor 12 h. The reaction was then partitioned with saturated ammoniumchloride and ethyl ether. The aqueous was then taken and basified andextracted with ethyl acetate the organic was then dried over magnesiumsulfate to give benzyl(1S,2R,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylate. The material wascarried forward without further purification. LCMS-ESI+ (m/z): [M+H]⁺:218.05.

Step 2. A solution of benzyl(1S,2R,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylate (0.4 g, 1.84 mmol)and N-ethyldiisopropylamine (0.9 mL, 5.5 mmol) in dichloromethane (20mL) was stirred at 0° C. as methyl chlorooxoacetate (0.25 mL, 2.7 mmol)was added dropwise. The reaction mixture was warmed to ambienttemperature and stirred for 1 h, at which point the reaction mixture wasquenched by pouring into a cooled aqueous solution of saturated sodiumbicarbonate. After the aqueous phase was thrice extracted withdichloromethane, the combined organic phases were washed with brine,dried over sodium sulfate, filtered, and solvent removed under reducedpressure to provide benzyl(1S,2R,5R)-3-(2-methoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylatewhich was carried forward without purification. LCMS-ESI+ (m/z): [M+H]⁺:303.99.

Step 3. A suspension of Benzyl(1S,2R,5R)-3-(2-methoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate(0.44 g, 1.5 mmol) and 10 wt % palladium on carbon (˜50% water, 0.15 g,0.7 mmol) in ethanol (20 mL) was stirred under one atmosphere hydrogenfor 2 h. Upon completion of reaction the crude mixture was filteredthrough celite with ethanol rinses and concentrated under reducedpressure to provide(1S,2R,5R)-3-(2-methoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylicacid which was carried forward without further purification. LCMS-ESI+(m/z): [M+H]⁺: 213.93.

Step 4. To a solution of oxalyl chloride (0.3 mL, 3.6 mmol) and 1% DMFin toluene (0.5 mL) in toluene (10 mL) was added crude(1S,2R,5R)-3-(2-methoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylicacid (0.7 mmol) in dichloromethane (4 mL) dropwise. The resultingsolution was stirred at ambient temperature for 1 h. The solution wasconcentrated and the residue was co-evaporated with toluene (10 mL). Theresulting residue was dried in vacuo for 30 min to give crude methyl2-((1S,2R,5R)-2-(chlorocarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoacetate.

After the above crude methyl2-((1S,2R,5R)-2-(chlorocarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoacetatewas dissolved in acetonitrile (4 mL), 2,6-di-tert-butylpyridine (0.24mL, 1.0 mmol) followed by ethyl 2-oxopent-3-ynoate (0.2 mL, 1.53 mmol)were added. The resulting solution was stirred at ambient temperaturefor 2 h. The mixture was concentrated and the residue was purified bysilica gel column chromatography eluting with 0-50% ethyl acetate inhexanes to give methyl(1aS,6bR)-6-(2-ethoxy-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺: 291.96.

Step 5. Methyl(1aS,6bR)-6-(2-ethoxy-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylate(0.1 g, 0.4 mmol) was dissolved in MeOH (5 mL), this was cooled to 0° C.and 1N NaOH (0.5 mL) was added the reaction was stirred for 30 mins tillcomplete, reaction was condensed down and evaporated twice with tolueneto give2-((1aS,6bR)-4-(methoxycarbonyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizin-6-yl)-2-oxoaceticacid which was carried forward without further purification. LCMS-ESI+(m/z): [M+H]⁺: 262.05.

Step 6. A solution2-((1aS,6bR)-4-(methoxycarbonyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizin-6-yl)-2-oxoaceticacid (60 mg, 0.228 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 129 mg, 0.342 mmol) and3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride (37mg, 0.228 mmol) in DMF (3 mL) was stirred at ambient temperature asN,N-diisopropylethylamine (0.11 mL, 0.68 mmol) was added. After 30 minat rt, the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous ammonium chloride (×2), saturated aqueous sodiumbicarbonate (×2), and brine (×1). After the aq. fractions were extractedwith ethyl acetate (×1), the organic fractions were combined, dried overmagnesium sulfate. After filtration, solvent was removed and the residuewas purified by silica gel column chromatography eluting 0-100% ethylacetate in hexanes to give methyl(1aS,6bR)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺: 408.22.

Step 7. To a solution(1aS,6bR)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylate(102 mg, 0.25 mmol) in THF (2 mL), MeOH (2 mL) and water (3 mL) wasadded 1 N LiOH (1.6 mL) at rt. The resulting mixture was stirred at 60°C. bath for 8 h. After the reaction mixture was diluted with water andacidified with 1 N HCl, the product was extracted with ethyl acetate(6×). The combined extracts were dried with magnesium sulfate,concentrated, and dried to give crude(1aS,6bR)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylicacid: LCMS-ESI+ (m/z): [M+H]⁺: 394.25.

Step 8. A solution of(1aS,6bR)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxylicacid (99 mg, 0.25 mmol), 3-chloro-4-fluoro aniline (35 mg, 0.25 mmol)and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 141 mg, 0.38 mmol) in DMF (3 mL) wasstirred at ambient temperature as N,N-diisopropylethylamine (0.13 mL,0.75 mmol) was added. After 1.25 h at rt, the reaction mixture wasdiluted with ethyl acetate (30 mL) and washed with saturated aqueousammonium chloride (×2), saturated aqueous sodium bicarbonate (×2), andbrine (×1). After the aq. fractions were extracted with ethyl acetate(×1), the organic fractions were combined, dried over magnesium sulfate.To the reaction was added 2,6-lutidine (0.1 mL, 1.0 mmol) this wascondensed to a thin film and heated till reaction was complete which waspurified via reverse phase HPLC 0-100% acetonitrile in water to give(1aS,6bR)-N-(3-chloro-4-fluorophenyl)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxamide(33).

Example 34(1aR,6bS)-N-(3-chloro-4-fluorophenyl)-6-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-5-methyl-1,1a,2,6b-tetrahydrocyclopropa[a]pyrrolizine-4-carboxamide(34)

Compound 34 was synthesized in a manner similar to Example 33, using(1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in place of(1S,2R,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid.

Example 35N-(3-cyano-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(35)

N-(3-cyano-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(35) was synthesized in a manner similar to Example 3 using3-cyano-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 367-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(36)

7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(36) was synthesized in a manner similar to Example 3 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 37N-(3-cyano-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(37)

N-(3-Chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(37) was synthesized in a manner similar to Example 29 using5-amino-2-fluorobenzonitrile in place of 3-chloro-4-fluoroaniline.

Example 38.(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(38)

Example 38 was synthesized in a manner similar to Example 5 using 3,4,5trifluoro aniline in place of 3-chloro-4-fluoro aniline.

Example 39(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(39)

Step 1. To a solution of methyl(1aR,6aR)-5-(2-ethoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(2.500 g, 8.58 mmol) in tetrahydrofuran (20 mL), methanol (20 mL), andwater (20 mL) was added 1 M lithium hydroxide (25.75 mL). After theresulting mixture was stirred at 65° C. for 8 h, the solution wasconcentrated to remove organic solvents, and the remained aqueoussolution was diluted with water, acidified, and then the product wasextracted with ethyl acetate. The extracts were dried over magnesiumsulfate. After filtration, solvent was removed to get(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₂H₁₂NO₅: 250.07; found:249.94.

Step 2. A solution of(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid (230 mg, 0.923 mmol), 1-ethynyl-3,3-difluorocyclobutan-1-aminiumtrifluoromethanesulfonate, which was prepared from benzyl(1-ethynyl-3,3-difluorocyclobutyl)carbamate (291.4 mg, 1.099 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (844.3 mg, 2.221 mmol) inN,N-dimethylformamide (5 mL) was stirred at 0° C. asN,N-diisopropylethylamine (1.6 mL, 9.185 mmol) was added. After 1 h, thereaction mixture was diluted with ethyl acetate (50 mL), washed with 10%aqueous citric acid (×2), saturated sodium bicarbonate (×2), and brine(×1). After the aqueous fractions were extracted with ethyl acetate(×1), the organic fractions were combined, dried over magnesium sulfate.After filtration, solvent was removed and the residue was purified bysilica gel column chromatography eluting 0-90% ethyl acetate in hexanesto give 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:1H NMR (400 MHz, Chloroform-d) δ 8.76 (dd, J=4.5, 1.4 Hz, 1H), 8.46 (dd,J=8.4, 1.4 Hz, 1H), 7.49 (d, J=1.4 Hz, 1H), 7.48-7.45 (m, 1H), 4.48 (t,J=6.0 Hz, 1H), 3.65 (dd, J=19.3, 6.9 Hz, 1H), 3.40 (d, J=19.2 Hz, 1H),3.20 (h, J=13.5, 12.9 Hz, 4H), 2.76 (s, 3H), 2.53 (s, 1H), 2.14 (p,J=6.2 Hz, 1H), 1.17 (dt, J=8.6, 6.1 Hz, 1H), 0.54-0.39 (m, 1H)):LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₁₉F₂N₆O₄: 481.14; found:480.86.

Step 3. To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(46.2 mg, 0.096 mmol) and 3-chloro-4-fluoroaniline (50.3 mg, 0.346 mmol)in dichloromethane (3 mL) was added 2,6-lutidine (0.05 mL, 0.429 mmol)and the resulting mixture was concentrated to an oil. The resulting oilwas heated at 100° C. bath for 22 h. The residue was dissolved indichloromethane and the insoluble material was filtered off. After theconcentration of the filtrate, the residue was purified by silica gelcolumn chromatography eluting 0-20% methanol in dichloromethane to give(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide:¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.26 (s, 1H), 7.89 (dd, J=6.8, 2.6Hz, 1H), 7.82 (s, 1H), 7.53 (ddd, J=9.0, 4.2, 2.6 Hz, 1H), 7.23 (t,J=9.1 Hz, 1H), 4.30 (tt, J=5.9, 1.9 Hz, 1H), 3.35 (dd, J=18.7, 6.8 Hz,1H), 3.25-3.05 (m, 5H), 2.79 (s, 1H), 2.49 (s, 3H), 2.12-2.02 (m, 1H),1.08 (dt, J=8.6, 5.8 Hz, 1H), 0.32-0.19 (m, 1H): ¹⁹F NMR (376 MHz,Acetonitrile-d₃) δ −88.61 (dp, J=198.8, 11.1 Hz, 1F), −93.14 (dp,J=198.9, 12.6 Hz, 1F), −123.80 (ddd, J=8.9, 6.8, 4.3 Hz, 1F): LCMS-ESI+(m/z): [M+H]⁺ calculated for C₂₄H₂₀ClF₃N₃O₃: 490.11; found: 490.17.

Step 4. A solution of(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(23.8 mg, 0.049 mmol) in N,N-dimethylformamide/methanol (9:1 mixture, 2mL) was stirred at 0° C. bath while argon gas was bubbled for 30 min. Tothe solution was added copper iodide (2.00 mg, 0.0105 mmol) under argonatmosphere and argon gas was bubbled further through the resultingmixture for 5 min. After azidotrimethylsilane (15 mg, 0.130 mmol) wasadded to the mixture, the resulting vial was kept tightly and themixture was stirred at 100° C. bath for 12 h. The reaction mixture wasdiluted with ethyl acetate and washed with 5% lithium chloride solution(×2). After the aqueous fractions were extracted with ethyl acetate(×1), the organic fractions were combined and dried over magnesiumsulfate. After filtration, solvent was removed and the residue waspurified by silica gel column chromatography 0-20% methanol indichloromethane to give(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(39).

Synthesis of 1-ethynyl-3,3-difluorocyclobutan-1-aminium chloride

Step A solution of benzyl (1-ethynyl-3,3-difluorocyclobutyl)carbamate(291.4 mg, 1.099 mmol) and anisole (0.36 mL, 3.312 mmol) indichloromethane (4 mL) was stirred at 0° C. bath astrifluoromethanesulfonic acid (0.2 mL, 2.260 mmol) was added. After 2min, the mixture was stirred at room temperature for 2.25 h. Thereaction mixture was diluted with water (˜40 mL) and washed with amixture of ether and hexane (1:3, 40 mL×1). The resulting aqueousfraction was concentrated using rotorvap to get crude1-ethynyl-3,3-difluorocyclobutan-1-aminium trifluoromethanesulfonate:LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₆H₈F₂N: 132.06; found: 131.91.

Example 40(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(40)

(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(40) was synthesized in a manner similar to Example 39 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 41(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(41)

Step 1. A solution of(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid (299.5 mg, 1.202 mmol) in N,N-dimethylformamide (6 mL) and methanol(0.6 mL) was stirred at 0° C. bath as and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1150.1 mg, 3.025 mmol) followed byN,N-diisopropylethylamine (1.5 mL, 8.612 mmol) were added. After 2 min,the mixture was stirred at room temperature. After 30 min, the reactionmixture was diluted with ethyl acetate and washed with 5% lithiumchloride solution (×2). After the aqueous fractions were extracted withethyl acetate (×1), the organic fractions were combined, dried overmagnesium sulfate. After filtration, solvent was removed and the residuewas purified by silica gel column chromatography eluting 0-100% ethylacetate in hexanes to get 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-methoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₁₆N₅O₅: 382.12; found:381.82.

Step 2. To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-methoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(138.7 mg, 0.364 mmol) and 5-amino-2-fluorobenzonitrile (153.8 mg, 1.130mmol) in dichloromethane (2 mL) was added 2,6-lutidine (0.17 mL, 1.460mmol) and the resulting solution was concentrated to yield an oil. Theresulting oil was heated at 70° C. bath for 20 h. After the residue wastriturated with N,N-dimethylformamide and filtered, the filtrate waspurified by reverse phase preparative HPLC (10-100% acetonitrile inwater, 0.1% trifluoroacetic acid) to get methyl2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate:¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.38 (s, 1H), 8.08 (dd, J=5.7, 2.7Hz, 1H), 7.89 (ddd, J=9.2, 4.8, 2.8 Hz, 1H), 7.33 (t, J=9.0 Hz, 1H),4.30 (t, J=5.9 Hz, 1H), 3.88 (s, 3H), 3.20 (dd, J=18.2, 6.8 Hz, 1H),3.06-2.94 (m, 1H), 2.51 (s, 3H), 2.15 (d, J=7.8 Hz, 1H), 1.11 (dt,J=8.7, 6.0 Hz, 1H), 0.39-0.29 (m, 1H): ¹⁹F NMR (376 MHz,Acetonitrile-d₃) δ −115.79-−115.91 (m): LCMS-ESI+ (m/z): [M+H]⁺calculated for C₂₀H₁₇FN₃O₄: 382.12; found: 382.14.

Step 3. A solution of methyl2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate(105.9 mg, 0.278 mmol) in tetrahydrofuran (5 mL), methanol (2 mL) andwater (4 mL) was stirred at room temperature as 1 N lithium hydroxide(0.56 mL) was added. After 30 min at room temperature, the reactionmixture was concentrated to remove most of the organic solvent, dilutedwith water, acidified with 1 N HCl, and the product was extracted withethyl acetate (×3). The combined extracts were dried over magnesiumsulfate. After filtration, solvent was removed to get2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid: LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₁₅FN₃O₄: 368.10; found:368.08.

Step 4. A solution of2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid (27.6 mg, 75.14 umol),3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine (14.8 mg, 84.98umol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (65.80 mg, 173.07 mmol) inN,N-dimethylformamide (1.5 mL) was stirred at room temperature asN,N-diisopropylethylamine (0.1 mL, 574.11 umol) was added. The reactionmixture was diluted with ethyl acetate (30 mL), washed with saturatedammonium chloride (×2), saturated sodium bicarbonate (×2), and brine(×1). After the aqueous fractions were extracted with ethyl acetate(×1), the organic fractions were combined and dried over magnesiumsulfate. After filtration, solvent was removed and the residue waspurified by reverse phase preparative HPLC (10-100% acetonitrile inwater, 0.1% trifluoroacetic acid) to get(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(41).

Example 42(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(42)

(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(42) was synthesized in a manner similar to Example 41 using3,4-difluoroaniline in place of 3-cyano-4-fluoroaniline.

Example 437-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(43)

7a-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(43) was synthesized in a manner similar to Example 29 using1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine hydrochloride in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminium chloride and3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 447-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(44)

Step 1. To a solution of (2-methoxy-2-oxoacetyl)-L-proline (8.75 g, 43.5mmol) in a 3:1 mixture of toluene:dichloromethane (80 mL) at 0° C. wasadded oxalyl chloride (7.4 mL, 86 mmol) dropwise, followed byN,N-dimethylformamide (0.1 mL). The reaction solution was allowed towarm to ambient temperature stirred for 2 hours at which point solventwas removed under reduced pressure and the residue redissolved inacetonitrile (80 mL). To this solution was added 2,6-lutidine (15 mL,129 mmol) followed by ethyl 2-oxopent-3-ynoate (5.1 mL, 39 mmol) and thereaction mixture was allowed to stir overnight. The reaction mixture wasthen concentrated under reduced pressure, diluted with ethyl acetate,sequentially washed with saturated aqueous solutions of ammoniumchloride then sodium chloride, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0-60% ethyl acetate in hexanes to affordmethyl7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 4.36 (q, J=7.1 Hz, 2H), 4.29 (dd,J=8.1, 6.6 Hz, 2H), 3.85 (s, 3H), 3.04-2.92 (m, 2H), 2.59 (s, 3H),2.52-2.46 (m, 2H), 1.39 (t, J=7.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₄H₁₈NO₅: 280.12; found: 280.03.

Step 2. To a 0° C. solution of methyl7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(5.54 g, 19.8 mmol) in ethanol (60 mL) was added a 4N aqueous solutionof sodium hydroxide (5 mL, 20 mmol). The reaction solution was allowedto stir at 0° C. for 5 minutes, at which point the mixture was acidifiedby addition of dilute aqueous hydrochloric acid. The mixture waspartitioned between water and ethyl acetate, and the aqueous phasethrice extracted to ethyl acetate. The combined organic phases werewashed with a saturated aqueous solution of ammonium chloride, driedover sodium sulfate, filtered, and concentrated under reduced pressureto afford2-(5-(methoxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid which was carried forward without further purification: ¹H NMR (400MHz, DMSO-d6) δ 4.21 (t, J=7.3 Hz, 2H), 3.77 (s, 3H), 2.90 (t, J=7.6 Hz,2H), 2.49 (s, 3H), 2.42 (p, J=7.6 Hz, 2H). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₂H₁₄NO₅: 252.09; found: 252.02.

Step 3. To a solution of2-(5-(methoxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (210 mg, 0.84 mmol) and 3,4-difluoroaniline (0.12 mL, 1.2 mmol) intetrahydrofuran (2.5 mL) was added a 1M solution of lithiumhexamethyldisilazide in tetrahydrofuran (2.5 mL, 2.5 mmol). The reactionmixture was allowed to stir for 18 hours and was subsequently quenchedwith a saturated aqueous solution of ammonium chloride. The aqueousphase was thrice extracted to diethyl ether and the combined organicphases sequentially washed with 1M aqueous hydrochloric acid (twice)then brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to afford2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid which was carried forward without further purification: LCMS-ESI+(m/z): [M+H]⁺ calculated for C₁₇H₁₅F₂N₂O₄: 349.10; found: 349.13.

Step 4. To a solution2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (449 mg, 1.29 mmol),1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide (233 mg, 1.42mmol), and N-methylmorpholine (0.55 mL, 5 mmol) in dimethylformamide (2mL) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (0.81 g, 2.1 mmol) and stirred for 30 minutes. Thecrude reaction mixture was then passed through a syringe filter andpurified by reverse phase preparative HPLC (10-100% acetonitrile inwater, 0.1% trifluoroacetic acid) to afford7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(44).

Example 45:(R)-7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizinecarboxamide (45)

Step 1 A mixture of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(15 g, 66 mmol) and cesium carbonate (32 g, 99 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature as benzylbromide (9.4 mL, 79 mmol) was added via syringe. After being allowed tostir overnight at room temperature, the reaction mixture was dilutedwith water (˜300 mL) and extracted three times with ethyl acetate. Thecombined extracts were washed once with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified viaflash chromatography (silica gel) to obtain 2-benzyl 1-(tert-butyl)(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate.

Step 2 A solution of 2-benzyl 1-(tert-butyl)(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (6.4 g, 20 mmol) indichloromethane (35 mL) was stirred at room temperature astrifluoroacetic acid (22 mL) was added. When LC/MS analysis indicatedthe complete removal of the protecting group, the mixture wasconcentrated under reduced pressure and(2S,4R)-2-((benzyloxy)carbonyl)-4-fluoropyrrolidin-1-iumtrifluoroacetate was carried forward. LCMS-ESI+ (m/z): [M+H]⁺ calculatedfor C₁₂H₁₅FNO₂: 224.1; found: 224.0

Step 3 A solution(2S,4R)-2-((benzyloxy)carbonyl)-4-fluoropyrrolidin-1-iumtrifluoroacetate (20 mmol assumed) in anhydrous dichloromethane (100 mL)was cooled in an ice-water bath under an atmosphere of argon.N,N-diisopropylethylamine (17 mL, 99 mmol) was added via syringe,followed by tert-butyl oxalyl chloride (3.79 g, 23 mmol). The ice-bathwas removed and the mixture was allowed to regain room temperature. Thereaction mixture was quenched with water. The aqueous phase wasextracted twice with dichloromethane. The combined organic extracts weredried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by flash chromatography(silica gel) to provide benzyl(2S,4R)-1-(2-(tert-butoxy)-2-oxoacetyl)-4-fluoropyrrolidine-2-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₂₃FNO₅: 352.2; found: 351.8

Step 4 A solution of benzyl(2S,4R)-4-fluoro-1-(2-tert-butoxy-2-oxoacetyl)pyrrolidine-2-carboxylate(6.76 g, 19 mmol) in ethanol (100 mL) was treated with small chunk ofdry ice and allowed to stir until the bubbling stopped (to degas thesolvent). The reaction mixture then treated with 10% palladium on carbon(wetted with approximately 55% water, 0.55 g, 0.23 mmol). The vessel wasstirred under 1 atmosphere of hydrogen for two hours. The mixture wasfiltered through a pad of Celite diatomaceous earth, and the filtratewas concentrated to give(2S,4R)-1-(2-(tert-butoxy)-2-oxoacetyl)-4-fluoropyrrolidine-2-carboxylicacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₁H₁₇FNO₅: 262.1; found:261.7

Step 5 To a mixture of oxalyl chloride (5.6 mL, 66 mmol) andN,N-dimethylformamide (5 mL of 1% (v/v) N,N-dimethylformamide intoluene) in toluene (60 mL) was added a solution of(2S,4R)-1-(2-(tert-butoxy)-2-oxoacetyl)-4-fluoropyrrolidine-2-carboxylicacid (13 mmol) in dichloromethane (26 mL+15 mL rinsate) dropwise viasyringe over 60 minutes. The resulting mixture was stirred at roomtemperature for 70 minutes, at which time the LC/MS analysis of analiquot in methanol revealed consumption of the starting acid withconcomitant formation of the methyl ester. The mixture was concentratedunder reduced pressure, and the putative tert-butyl2-((2S,4R)-2-(chlorocarbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoacetate wascarried forward.

Step 6 Crude tert-butyl2-((2S,4R)-2-(chlorocarbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoacetate (13mmol assumed) was dissolved in acetonitrile (50 mL) and treated with2,6-di-tert-butylpyridine (4.4 mL, 20 mmol) and then dropwise with ethyl2-oxopent-3-ynoate (1.8 mL, 14 mmol). The resulting solution was stirredat room temperature for 4.5 hours and then refrigerated overnight. Themixture was purified by flash chromatography (silica gel) to providetert-butyl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₂₃FNO₅: 340.2; found: 340.0

Step 7 Tert-butyl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(0.99 g, 2.9 mmol) was taken up in DCM (15 mL) and via syringe with TFA(3.3 mL, 43 mmol, 15 eq). After 80 minutes of stirring at roomtemperature, the mixture was added to approximately 100 mL of saturatedaqueous sodium hydrogen carbonate solution. The aqueous phase wasextracted once with dichloromethane and then was cooled in an ice-waterbath and then acidified to pH 2-3 by the portionwise addition of ca. 20%aqueous sulfuric acid. The resulting suspension was extracted threetimes with ethyl acetate. The combined extracts were washed once withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure to give(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₃H₁₅FNO₅: 284.1; found:284.0

Step 8 A solution of(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid (0.58 g, 2.1 mmol) in N,N-dimethylformamide (10 mL) was treatedsuccessively with N,N-diisopropylethylamine (1.1 mL, 6.2 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 0.86 g. 2.3 mmol). After 30 minutes,an additional portion of HATU (0.10 g, 0.26 mmol) was added. Followingthe passage of 15 minutes, the mixture was partitioned between ethylacetate and water. The aqueous phase was extracted three times withethyl acetate. The combined extracts were washed once with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by flash chromatography (silica gel) to provide3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₁₇FN₅O₅: 402.1; found: 401.9

Step 9 A suspension of 3-chloro-4-fluoroaniline (0.12 g, 0.79 mmol) and3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(0.11 g, 0.26 mmol) in dichloromethane was treated with 2,6-lutidine(0.12 mL, 1.1 mmol). The mixture was concentrated under reduced pressureand then was heated overnight at 80° C. The mixture was purified byflash chromatography (silica gel) to provide ethyl(R)-2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₁₈ClF₂N₂O₄: 411.1; found:411.2

Step 10 A solution of ethyl(R)-2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate(84 mg, 0.20 mmol) in tetrahydrofuran/methanol (1:1, 2 mL) was treatedwith water (0.5 mL). Additional volumes of tetrahydrofuran (4 mL) andwater (1.5 mL) were added. The suspension was heated and sonicated untilhomogenous and then was transferred to an ice-water bath. Lithiumhydroxide monohydrate (13 mg, 0.31 mmol) was added in a single portion.When the reaction was deemed complete by LC/MS analysis, it wasacidified with 20% aqueous sulfuric acid. The acidified mixture wasextracted three times with ethyl acetate. The combined extracts werewashed once with saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and concentrated to dryness underreduced pressure to provide(R)-2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₁₄ClF₂N₂O₄: 383.1;found: 383.1

Step 11 A mixture of 1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-aminedihydrochloride (70 mg, 0.35 mmol) and(R)-2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (78 mg, 0.20 mmol) was taken up in N,N-dimethylformamide (3 mL) andtreated successively with N,N-diisopropylethylamine (0.50 mL, 2.9 mmol)and HATU (170 mg, 0.45 mmol). After 40 minutes, additional portions of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloride (70 mg,0.35 mmol) and HATU (170 mg, 0.45 mmol) were added. After 48 hours, themixture was diluted with methanol (3 mL), treated with piperidine (0.3mL), and concentrated under reduced pressure. The residue was purifiedby preparative reverse-phase HPLC (5-80% acetonitrile in water, 0.1% TFAbuffer) to provide(R)-7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(45).

Example 46(S)-7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(46)

(S)-7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(46) was prepared in a manner analogous to Example 45 using(2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid inplace of(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid.

Example 477-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(47)

7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(47) was synthesized in a manner similar to Example 29 using4-fluoroaniline in place of 3,4-difluoroaniline and using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminiumchloride.

Example 48:(R)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-2-fluoro-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(48)

Step 1 A suspension of 4-fluoroaniline (98 mg, 0.88 mmol) and3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(0.12 g, 0.29 mmol) in dichloromethane (5 mL) was treated with2,6-lutidine (0.14 mL, 1.2 mmol). The mixture was concentrated underreduced pressure and then was heated overnight at 80° C. The mixture waspurified by flash chromatography (silica gel) to provide ethyl(R)-2-(2-fluoro-5-((4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₁₈F₂N₂O₄: 377.1; found: 377.2

Step 2 A solution of ethyl(R)-2-(2-fluoro-5-((4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate(83 mg, 0.22 mmol) in tetrahydrofuran/water (1:1, 6 mL) was treated withlithium hydroxide monohydrate (11 mg, 0.27 mmol). When the reaction wasdeemed complete by LC/MS analysis, it was acidified with 20% aqueoussulfuric acid. The acidified mixture was extracted three times withethyl acetate. The combined extracts were washed once with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure toprovide(R)-2-(2-fluoro-5-((4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₁₅F₂N₂O₄: 349.1; found:349.1

Step 3 A mixture of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine (52 mg, 0.30mmol) and(R)-2-(2-fluoro-5-((4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (76 mg, 0.22 mmol) was taken up in N,N-dimethylformamide (3 mL) andtreated successively with N,N-diisopropylethylamine (0.30 mL, 1.7 mmol)and HATU (0.24 g, 0.64 mmol). After 30 minutes, the mixture was dilutedwith methanol (˜3 mL), treated with 10 drops of piperidine, andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC (10-80% acetonitrile in water, 0.1% TFAbuffer) to provide(R)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-2-fluoro-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(48).

Example 49:(R)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(49)

Step 1 A suspension of 3,4-difluoroaniline (0.11 mL, 1.1 mmol) and3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(0.14 g, 0.35 mmol) in dichloromethane (5 mL) was treated with2,6-lutidine (0.16 mL, 1.4 mmol). The mixture was concentrated underreduced pressure and then was heated overnight at 80° C. The mixture waspurified by flash chromatography (silica gel) to provide ethyl(R)-2-(5-((3,4-difluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₁₈F₃N₂O₄: 395.1; found: 395.2

Step 2 A solution of ethyl(R)-2-(5-((3,4-difluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetate(0.14 g, 0.35 mmol) in tetrahydrofuran/water (5:2, 7 mL) was treatedwith lithium hydroxide monohydrate (30 mg, 0.72 mmol). When the reactionwas deemed complete by LC/MS analysis, it was acidified with 20% aqueoussulfuric acid. The acidified mixture was extracted three times withethyl acetate. The combined extracts were washed once with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure toprovide(R)-2-(5-((3,4-difluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₇H₁₄F₃N₂O₄: 367.1; found:367.1

Step 3 A mixture of1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide (100 mg, 0.50mmol) and(R)-2-(5-((3,4-difluorophenyl)carbamoyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (125 mg, 0.34 mmol) was taken up in N,N-dimethylformamide (3 mL)and treated successively with N,N-diisopropylethylamine (0.30 mL, 1.7mmol) and HATU (0.26 g, 0.68 mmol). The mixture was partitioned betweenethyl acetate and saturated aqueous sodium hydrogen carbonate solution.The aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were subsequently washed successively with 10%aqueous hydrochloric acid, water, and a 1:1 mixture of saturated aqueoussodium hydrogen carbonate and sodium chloride solutions. The organicswere dried over anhydrous magnesium sulfate, filtered, concentrated, andconcentrated. The residue was purified by preparative reverse-phase HPLC(15-90% acetonitrile in water, 0.1% TFA buffer) to provide(R)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(49).

1-(2-Methyl-2H-tetrazol-5-yl)cyclopropan-1-amine hydrochloride

Step 1. A vigorously stirred mixture of benzyl(1-cyanocyclopropyl)carbamate (1.92 g, 8.89 mmol), sodium azide (870 mg,13 mmol), and ammonium chloride (710 mg, 13 mmol) inN,N-dimethylformamide (20 mL) was heated to 110° C. in a sand bath.After 16 h, the resulting mixture was allowed to cool to ambienttemperature and was concentrated under reduced pressure. The residue waspurified by was purified by reverse phase preparative HPLC (10-100%acetonitrile in water, 0.1% trifluoroacetic acid) to give benzyl(1-(2H-tetrazol-5-yl)cyclopropyl)carbamate.

Steps 2-3. Diazomethyltrimethylsilane solution (2.0 M in hexanes, 5.1mL, 10 mmol) was added via syringe over 5 min to a stirred solution ofbenzyl (1-(2H-tetrazol-5-yl)cyclopropyl)carbamate (2.20 g, 8.49 mmol) intoluene (70 mL) and methanol (20 mL) at ambient temperature. After 20min, acetic acid was added dropwise via syringe until gas evolutionceased and the yellow color dissipated from the reaction mixture. Theresidue was dissolved in ethanol (70 mL), palladium on activated carbon(10% wt/wt, 2 g, 2 mmol) was added, and the resulting mixture wasstirred vigorously at ambient temperature. After 2 min, the resultingmixture was placed under 1 atm of hydrogen gas. After 90 min, thereaction mixture was filtered through celite, and the filter cake wasextracted with ethyl acetate (80 mL). Hydrogen chloride solution (4 M in1,4-dioxane, 3.0 mL) was added via syringe to the filtrate, and theresulting mixture was swirled vigorously for 1 min and then concentratedunder reduced pressure to give1-(2-methyl-2H-tetrazol-5-yl)cyclopropan-1-amine hydrochloride.

Example 50.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(2-methyl-2H-tetrazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(2-methyl-2H-tetrazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(50) was synthesized in a manner similar to Example 2 using a mixture of1-(2-methyl-2H-tetrazol-5-yl)cyclopropan-1-amine hydrochloride and1-(1-methyl-1H-tetrazol-5-yl)cyclopropan-1-amine hydrochloride in placeof (R)-trifluoroisopropylamine.

Example 51.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(5-methyl-4H-1,2,4-triazol-3-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

1-(5-methyl-4H-1,2,4-triazol-3-yl)cyclopropan-1-amine was synthesizedfrom tert-butyl hydrazinecarboxylate and1-(((benzyloxy)carbonyl)amino)cyclopropane-1-carboxylic acid in 4 stepsfollowing the procedure describe in WO 2009070485A1.

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(5-methyl-4H-1,2,4-triazol-3-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(51) was synthesized in a manner similar to Example 6 Step 6 using1-(5-methyl-4H-1,2,4-triazol-3-yl)cyclopropan-1-amine in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 52(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

Step 1 and 2 Methyl(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylatewas synthesized in a manner similar to Example 54, step 4, using1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amine hydrochloride in place of3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride: ¹HNMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.60 (s, 1H), 4.43 (d, J=6.3Hz, 1H), 3.89 (s, 3H), 3.56-3.39 (m, 1H), 3.23 (d, J=18.9 Hz, 1H), 2.56(s, 3H), 2.04 (s, 1H), 1.49 (s, 2H), 1.36 (s, 2H), 1.09 (s, 1H), 0.29(s, 1H). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₂₀N₅O₄: 370.2;found: 370.1

Step 3 A mixture of methyl(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(56.5 mg, 0.153 mmol) and potassium carbonate (42.3 mg, 0.306 mmol) inN,N-dimethylformamide (1.5 mL) was stirred at ambient temperature as2-(trimethylsilyl)ethoxymethyl chloride (32 uL, 0.184 mmol) was added.The resulting mixture was stirred at ambient temperature for 1.5 h. Thereaction mixture was diluted with ethyl acetate and washed with water(×1). After the aq. fractions were extracted with ethyl acetate (×1),the combined organic fractions were dried with magnesium sulfate. Afterfiltration, solvent was removed and the residue was purified by silicagel column chromatography eluting 0-100% ethyl acetate in hexanes togive the pure major isomer of ((2-(trimethylsilyl)ethoxy)methylatedmethyl(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 1H), 7.51 (s, 1H), 5.56 (s,2H), 4.43 (ddt, J=6.0, 3.8, 1.8 Hz, 1H), 3.89 (s, 3H), 3.66-3.56 (m,2H), 3.51 (dd, J=19.0, 6.9 Hz, 1H), 3.24 (dt, J=19.1, 1.2 Hz, 1H), 2.57(s, 3H), 2.13-1.92 (m, 1H), 1.52-1.45 (m, 2H), 1.36-1.29 (m, 2H), 1.07(dt, J=8.6, 6.0 Hz, 1H), 0.94-0.86 (m, 2H), 0.28 (ddd, J=6.4, 5.1, 2.0Hz, 1H), −0.03 (s, 9H). LCMS-ESI+ (m/z): [M+H]⁺ calculated forC₂₄H₃₄N₅O₅Si: 500.2; found: 500.0

Step 4 A solution of the above pure major isomer of((2-(trimethylsilyl)ethoxy)methylated methyl(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(29.9 mg, 0.060 mmol) in tetrahydrofuran (0.5 mL), methanol (0.5 mL) andwater (1 mL) was stirred as 1 N lithium hydroxide (0.185 mL) was added.The mixture was refluxed at 70° C. bath for 6 h. The reaction mixturewas diluted with brine, acidified with 1 N hydrochloric acid (˜0.19 mL),and transferred to a separatory funnel using brine and ethyl acetate.After two fractions were separated, the aqueous fraction was extractedwith ethyl acetate (×1). The combined organic fractions were dried withmagnesium sulfate. After filtration, solvent was removed to give crude(1aR,6aR)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₃₂N₅O₅Si: 486.2; found:486.0

A solution of the crude(1aR,6aR)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid (0.060 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (35.6 mg, 0.094 mmol) inN,N-dimethylformamide (1.5 mL) was stirred at ambient temperature asN,N-diisopropylethylamine (0.05 mL, 0.287 mmol) was added. After 1 h,the reaction mixture was diluted with ethyl acetate and washed withaqueous ammonium chloride (×2), aqueous sodium bicarbonate (×2), andbrine (×1). After the aq. fractions were extracted with ethyl acetate(×1), the organic fractions were combined, dried with magnesium sulfate.After filtration, solvent was removed and the residue was co-evaporatedwith toluene (×2), dried in vacuum for 30 min to give the crude3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate.LCMS-ESI+ (n/z): [M+H]⁺ calculated for C₂₈H₃₄N₉O₅Si: 604.3; found: 604.0

To a solution of the crude 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylateand 3-chloro-4-fluoroaniline (36 mg, 0.247 mmol) in2-methyltetrahydrofuran (2 mL) was added 2,6-lutidine (0.05 mL, 0.429mmol) at ambient temperature. The resulting mixture was kept tightly andheated at 80° C. for 111.5 h. After the reaction mixture wasconcentrated, the residue was purified by by silica gel columnchromatography eluting 0-100% ethyl acetate in hexanes to get somewhatimpure product. The impure product was further purified by silica gelcolumn chromatography eluting 0-6% methanol in dichloromethane to give(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamidecontaining minor impurities: ¹H NMR (400 MHz, Chloroform-d) δ 7.81 (dd,J=6.5, 2.6 Hz, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.38 (ddd,J=8.9, 4.0, 2.8 Hz, 1H), 7.12 (t, J=8.7 Hz, 1H), 5.56 (s, 2H), 4.53-4.41(m, 1H), 3.67-3.57 (m, 2H), 3.51 (dd, J=19.0, 6.9 Hz, 1H), 3.31-3.16 (m,1H), 2.61 (s, 3H), 2.06 (p, J=6.0 Hz, 1H), 1.54-1.45 (m, 2H), 1.38-1.30(m, 2H), 1.25 (s, 1H), 1.10 (dt, J=8.6, 6.0 Hz, 1H), 0.96-0.86 (m, 2H),0.35-0.26 (m, 1H), −0.03 (s, 9H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−120.73 (ddd, J=8.7, 6.5, 4.1 Hz). LCMS-ESI+ (n/z): [M+H]⁺ calculatedfor C₂₉H₃₅ClFN₆O₄Si: 613.2; found: 613.0

Step 5(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-4-methyl-5-(2-oxo-2-((1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(11.4 mg, 0.019 mmol) was dissolved in dichloromethane (1 mL) andethanol (0.1 mL) and stirred at rt as trifluoroacetic acid (0.25 mL,3.265 mmol) was added. The resulting mixture was stirred at ambienttemperature for 9 h. After the reaction mixture was concentrated, theresidue was dissolved in N,N-dimethylformamide, filtered, and purifiedby preparative HPLC (column, Gemini 10u C18 110A, AXI/; 250×21.2 mm)eluting 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA). The productcontaining fractions were combined and freeze-dried to give(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide.

Example 53.7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(53) was synthesized in a manner similar to Example 29 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluouroaniline.

Example 54.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(54) was synthesized in a manner similar to Example 5 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 55.7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(55) was synthesized in a manner similar to Example 29 using2-(difluoromethyl)pyridin-4-amine in place of 3-chloro-4-fluouroaniline.

Example 56(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

Step 1 and 2 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylatewas synthesized in a manner similar to Example 5, step 4 and 5, using1-ethynylcyclopropan-1-amine hydrochloride in place of3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride: ¹HNMR (400 MHz, Chloroform-d) δ 8.75 (dd, J=4.5, 1.4 Hz, 1H), 8.46 (dd,J=8.4, 1.4 Hz, 1H), 7.49 (s, 1H), 7.46 (dd, J=8.4, 4.5 Hz, 1H), 4.47(tt, J=5.9, 1.9 Hz, 1H), 3.68 (dd, J=19.4, 6.9 Hz, 1H), 3.48-3.36 (m,1H), 2.74 (s, 3H), 2.19 (s, 1H), 2.17-2.08 (m, 1H), 1.42-1.32 (m, 2H),1.23-1.11 (m, 3H), 0.45 (ddd, J=6.5, 5.2, 2.1 Hz, 1H). LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₂₂H₁₉N₆O₄: 431.2; found: 430.9

Step 3 To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(59.6 mg, 0.138 mmol) and 2-(difluoromethyl)pyridin-4-amine (61.2 mg,0.425 mmol) in dichloromethane (3 mL) was added 2,6-lutidine (0.07 mL,0.601 mmol) and the resulting mixture was concentrated to an oil. Theresulting oil was heated at 60° C. bath for 4 h, and at 100° C. bath for17 h. The reaction mixture was was purified by silica gel columnchromatography eluting 0-20% methanol in dichloromethane to get(1aR,6aR)-N-(2-(difluoromethyl)pyridin-4-yl)-5-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide:¹H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J=5.5 Hz, 1H), 7.83 (d, J=2.1Hz, 1H), 7.78 (s, 1H), 7.75 (dd, J=5.7, 2.0 Hz, 1H), 7.44 (s, 1H), 6.63(t, J=55.4 Hz, 1H), 4.48 (dd, J=6.9, 5.0 Hz, 1H), 3.58 (dd, J=19.2, 6.9Hz, 1H), 3.39-3.22 (m, 1H), 2.61 (s, 3H), 2.18 (s, 1H), 2.15-2.03 (m,1H), 1.42-1.32 (m, 2H), 1.20-1.06 (m, 3H), 0.32 (ddd, J=6.4, 5.1, 2.1Hz, 1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −116.58 (d, J=55.3 Hz).LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₂₁F₂N₄O₃: 439.2; found: 439.2

Step 4 A solution of(1aR,6aR)-N-(2-(difluoromethyl)pyridin-4-yl)-5-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(22.2 mg, 0.051 mmol) in N,N-dimethylformamide/methanol (9:1 mixture, 2mL) was placed in a thick wall tube containing copper iodide (1.4 mg,7.351 umol) and azidotrimethylsilane (30 mg, 0.260 mmol) was added tothe mixture. The resulting tube was kept tightly and the mixture wasstirred at 100° C. bath for 12 h. The reaction mixture was diluted withethyl acetate and washed with water (×2). After the aq. fractions wereextracted with ethyl acetate (×1), the organic fractions were combined,dried with magnesium sulfate. After filtration, solvent was removed andthe residue was purified by silica gel column chromatography eluting0-14% methanol in dichloromethane to get impure product. The impureproduct was further purified by Preparative HPLC (column, Gemini 10u C18110A, AXI/; 250×21.2 mm) eluting 10-90% acetonitrile (0.1% TFA) in water(0.1% TFA) to get(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide.

Example 57.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-4-methyl-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(57) was synthesized in a manner similar to Example 38 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 58.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(58)

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(58) was synthesized in a manner similar to Example 30 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 59.7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(59) was synthesized in a manner similar to Example 29 using2-(difluoromethyl)-3-fluoropyridin-4-amine in place of3-chloro-4-fluouroaniline.

Example 60.N-(3-chloro-4-fluorophenyl)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(60) was synthesized in a manner similar to Example 29 using1-ethynyl-3,3-difluorocyclobutan-1-amine trifluoromethanesulfonate inplace of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 61.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(61) was synthesized in a manner similar to Example 42 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 62.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(62) was synthesized in a manner similar to Example 56 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 63(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(63)

(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(63) was synthesized in a manner similar to Example 56 using2-(difluoromethyl)-3-fluoropyridin-4-amine in place of2-(difluoromethyl)pyridin-4-amine.

Example 64.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(64) was synthesized in a manner similar to Example 2 using1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-amine in place ofR-trifluoroisopropylamine.

Example 65.6-methyl-7-(2-((1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

6-methyl-7-(2-((1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(65) was synthesized in a manner similar to Example 64 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 66.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1-phenylcyclopropyl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1-phenylcyclopropyl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(66) was synthesized in a manner similar to Example 2 using1-phenylcyclopropan-1-amine in place of R-trifluoroisopropylamine.

Example 67.6-methyl-7-(2-oxo-2-((1-phenylcyclopropyl)amino)acetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

6-methyl-7-(2-oxo-2-((1-phenylcyclopropyl)amino)acetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(67) was synthesized in a manner similar to Example 66 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 68.(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1,3,4-thiadiazol-2-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(68) was synthesized in a manner similar to Example 63 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 69.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(69)

Step 1: Lithium hydroxide (1N, 12.9 mL, 12.9 mmol) was added to asolution of methyl7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(1.2 g, 4.29 mmol) in methanol. The mixture warmed and all materialdissolved. The solution was heated at 60° C. for 8 h. The reaction wasdiluted with water (10 mL) and the majority of the methanol was removedunder reduced pressure. The aqueous phase was extracted with ethylacetate (3×50 mL). The aqueous phase was acidified with hydrochloricacid (1N, 14 mL) and extracted with ethyl acetate (3×50 mL). Thecombined acidic extracts were washed with brine (50 mL), dried oversodium sulfate. The solvent was removed under reduced pressure. Theresidue was co-evaporated with ethyl acetate (2×20 mL) and subjected tohigh vacuum for 2 h, providing7-(carboxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid. ¹H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 4.20 (t, J=7.3 Hz, 2H),2.89 (t, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.40 (p, J=7.5 Hz, 2H).

Step 2: N,N-Diisoprpylethylamine (1.83 mL, 10.5 mmol) was added to asuspension of7-(carboxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid (500 mg, 2.11 mmol) and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.76 g, 4.64 mmol) in dichloromethane. After2 min 1-ethynylcyclopropan-1-amine 2,2,2-trifluoroacetate (617 mg, 3.16mmol) was added. After 30 m the reaction was diluted with ethyl acetate(50 mL) and washed with water (20 mL), saturated ammonium chloride (3×20mL), saturated sodium bicarbonate (3×20 mL) and brine (20 mL). Theorganic phase was dried over sodium sulfate and the solvent was removedunder reduced pressure. The residue was subjected to flashchromatography (0-100% ethyl acetate/hexanes). The fractions containingproduct were combined and the solvent was removed under reducedpressure, providing 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate.¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.18 (s, 1H), 8.83 (dd, J=4.5,1.3 Hz, 1H), 8.73 (dd, J=8.4, 1.4 Hz, 1H), 7.65 (dd, J=8.5, 4.5 Hz, 1H),4.35 (t, J=7.3 Hz, 2H), 4.19 (s, 1H), 3.08 (s, 1H), 3.07-3.00 (m, 2H),2.89 (t, J=7.6 Hz, 1H), 2.66 (s, 3H), 2.37 (t, J=7.3 Hz, 1H), 1.21-1.11(m, 2H), 1.10-0.99 (m, 2H).

Step 3: 2,6-Lutidine (55.5 uL, 0.4785 mmol) 3-fluoroaniline (34.5 uL,0.358 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(50 mg, 0.119 mmol) were dissolved in dichloromethane (3 mL). Themajority of the dichloromethane was removed under reduced pressure. Theoil was heated neat at 100° C. for 18 h-solid formed. Dichloromethane (3mL) was added and the mixture was stirred under homogenous. The solidwas isolated by filtration and subjected to high vacuum for 30 minutes,providing7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-N-(3-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.¹H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.21 (s, 1H), 7.65-7.56 (m,1H), 7.36 (dt, J=22.9, 8.1 Hz, 2H), 6.89 (t, J=8.4 Hz, 1H), 4.13 (t,J=7.3 Hz, 2H), 3.04 (s, 1H), 2.92 (t, J=7.5 Hz, 2H), 2.41 (s, 5H),1.19-1.11 (m, 2H), 1.07-0.97 (m, 2H).

Step 4: Azidomethyl pivalate (15.2 uL, 0.0995 mmol) was added to amixture of7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-N-(3-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(35.6 mg, 0.0905 mmol) Copper(I)-thiophene-2-carboxylate (3.45 mg,0.00181 mmol) in methanol 2 mL) and dimethylformamide (1 mL). After 30min sodium hydroxide (1N, 136 uL, 0.136 mmol) was added. After 15 minthe reaction was neutralized with hydrochloric acid (1N, 136 uL, 0.00181mmol). The volatiles were removed under reduced pressure. The residuewas dissolved in N,N-dimethylformamide. The turbid solution was syringefiltered and subjected to preparative HPLC (eluant: 0.1% trifluoroaceticacid in water/0.1% trifluoroacetic acid in acetonitrile). The fractionscontaining product were combined and subjected to lyophilizationproviding7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.¹H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.36 (s, 1H), 7.65-7.52 (m,2H), 7.44-7.30 (m, 2H), 6.89 (td, J=8.5, 8.1, 2.2 Hz, 1H), 4.12 (t,J=7.3 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H), 2.41 (s, 3H), 2.40-2.34 (m, 2H),1.31-1.23 (m, 2H), 1.20 (t, J=3.2 Hz, 2H).

Example 70.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(70)

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using 4-fluoroanilinein place of 3-fluoroaniline.

Example 71.(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-N-(3-chloro-4-fluorophenyl)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(71) was synthesized in a manner similar to Example 5 using3-amino-3-methylthietane 1,1-dioxide in place of3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Example 72.(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-N-(3-cyano-4-fluorophenyl)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(72) was synthesized in a manner similar to Example 5 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochlorideand 5-amino-2-fluorobenzonitrile in place of 3-chloro-4-fluoroaniline.

Example 73.(1aR,6aR)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-4-methyl-5-(2-((3-methyl-1,1-dioxidothietan-3-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(73) was synthesized in a manner similar to Example 5 using1-(1,3,4-thiadiazol-2-yl)cyclopropan-1-amine hydrogen bromide in placeof 3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochlorideand 3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 74.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 26 using 3-chloroanilinein place of 3-fluoroaniline.

Example 75.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyanophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyanophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using 3-cyanoanilinein place of 3-fluoroaniline.

Example 76.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,5-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,5-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3,5-difluoroaniline in place of 3-fluoroaniline.

Example 77.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3-(difluoromethyl)-4-fluoroaniline in place of 3-fluoroaniline.

Example 78.(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

Step 1 A solution of methyl(1aR,6aR)-5-(2-ethoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(2730 mg, 9.372 mmol) was stirred in tetrahydrofuran (20 mL), methanol(20 mL), and 1 N lithium hydroxide (28 mL) and the resulting solutionwas stirred at 60° C. for 8 h. After the reaction mixture wasconcentrated to remove most of the organic solvents, the residualsolution was diluted with water (˜30 mL) and washed with diethyl ether(×1), acidified with 1 N hydrochloric acid (˜28 mL), and the product wasextracted with ethyl acetate (×1). The aqueous fraction was saturatedwith NaCl and extracted with ethyl acetate (×1). After the organicfractions were washed with brine (×1), two organic fractions werecombined, dried with magnesium sulfate. After filtration, solvent wasremoved and dried in vacuum overnight to give(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₂H₁₂NO₅: 250.1; found:249.9

Step 2(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid (201.3 mg, 0.808 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (839.7 mg, 2.209 mmol) were dissolved inN,N-dimethylformamide (4 mL) and methanol (0.4 mL) followed byN,N-diisopropylethylamine (0.98 mL, 5.626 mmol) at ambient temperature.After 30 min, the reaction mixture was diluted with ethyl acetate (˜40mL) and washed with 5% LiCl solution (×2). After the aqueous fractionswere extracted with ethyl acetate (×1), the organic fractions werecombined, dried with magnesium sulfate. After filtration, solvent wasremoved and the residue was purified by silica gel column chromatographyeluting 0-100% ethyl acetate in hexanes to give3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-methoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 8.75 (dd, J=4.5, 1.4 Hz, 1H), 8.46 (dd,J=8.4, 1.4 Hz, 1H), 7.47 (dd, J=8.4, 4.5 Hz, 1H), 4.47 (ddt, J=7.8, 5.9,1.9 Hz, 1H), 3.93 (s, 3H), 3.34 (dd, J=18.8, 6.9 Hz, 1H), 3.21-3.11 (m,1H), 2.74 (s, 3H), 2.22-2.12 (m, 1H), 1.20 (dt, J=8.7, 6.1 Hz, 1H), 0.51(ddd, J=6.7, 5.1, 2.1 Hz, 1H). LCMS-ESI+ (m/z): [M+H]⁺ calculated forC₁₈H₁₆N₅O₅: 382.1; found: 381.8

Step 3 To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-methoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(51.3 mg, 0.135 mmol) and 2-(difluoromethyl)pyridin-4-amine (63.1 mg,0.438 mmol) in dichloromethane (5 mL) was added 2,6-lutidine (0.07 mL,0.601 mmol) and the resulting mixture was concentrated to an oil. Theresulting oil was heated at 100° C. bath for 21.5 h. The tar wasdissolved in dichloromethane and the soluble material was purified bysilica gel column chromatography eluting 0-100% ethyl acetate in hexanesfollowed by another silica gel column chromatography eluting 0-7%methanol in dichloromethane to give methyl2-((1aR,6aR)-3-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate:¹H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J=5.5 Hz, 1H), 7.93-7.80 (m,2H), 7.73 (dd, J=5.6, 2.3 Hz, 1H), 6.62 (t, J=55.4 Hz, 1H), 4.49 (tt,J=6.0, 1.9 Hz, 1H), 3.90 (s, 3H), 3.23 (dd, J=18.3, 6.8 Hz, 1H), 3.04(d, J=18.3 Hz, 1H), 2.62 (d, J=3.0 Hz, 3H), 2.21-2.07 (m, 1H), 1.18 (dt,J=8.8, 6.2 Hz, 1H), 0.40 (qd, J=6.1, 4.9, 2.3 Hz, 1H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −116.61 (d, J=55.7 Hz). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₉H₁₈N₃O₄: 390.1; found: 390.1

Step 4 A solution of methyl2-((1aR,6aR)-3-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate(18.1 mg, 46.49 umol) in tetrahydrofuran (0.3 mL), methanol (0.3 mL) andwater (0.5 mL) was stirred at ambient temperature as 1 N lithiumhydroxide (0.1 mL) was added. After 30 min, the reaction mixture wasconcentrated to remove most of the organic solvent, diluted with water,acidified with 1 N hydrochloric acid, and the product was extracted withethyl acetate (×2). The combined extracts were dried with magnesiumsulfate. After filtration, solvent was removed and dried in vacuum togive crude2-((1aR,6aR)-3-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₈H₁₆N₃O₄: 376.1; found:376.1

A solution of the crude2-((1aR,6aR)-3-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid, 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine (12.1 mg,69.48 umol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (46.80 mg, 123.1 umol) inN,N-dimethylformamide (1 mL) was stirred at ambient temperature asN,N-diisopropylethylamine (0.06 mL, 344.5 umol) was added. After 30 min,the reaction mixture was diluted with ethyl acetate (30 mL), washed withaq. ammonium chloride (×2), aq. sodium bicarbonate (×2), and brine (×1).After the aq. fractions were extracted with ethyl acetate (×1), theorganic fractions were combined, dried with magnesium sulfate. Afterfiltration, solvent was removed and the residue was purified bypreparative HPLC (column, Gemini 10u C18 110A, AXI/; 250×21.2 mm)eluting 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide.

Example 79.(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

Step 1 To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-methoxy-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate(138.7 mg, 0.364 mmol) and 5-amino-2-fluorobenzonitrile (153.8 mg, 1.130mmol) in dichloromethane (2 mL) was added 2,6-lutidine (0.17 mL, 1.460mmol) and the resulting mixture was concentrated to an oil. Theresulting oil was heated at 70° C. bath for 20 h. After the residue wasdissolved in N,N-dimethylformamide, the product was purified bypreparative HPLC (column, Gemini 10u C18 110A, AXI/; 250×21.2 mm)eluting 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA) to get methyl2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate:¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.38 (s, 1H), 8.08 (dd, J=5.7, 2.7Hz, 1H), 7.89 (ddd, J=9.2, 4.8, 2.8 Hz, 1H), 7.33 (t, J=9.0 Hz, 1H),4.30 (t, J=5.9 Hz, 1H), 3.88 (s, 3H), 3.20 (dd, J=18.2, 6.8 Hz, 1H),3.06-2.94 (m, 1H), 2.51 (s, 3H), 2.15 (d, J=7.8 Hz, 1H), 1.11 (dt,J=8.7, 6.0 Hz, 1H), 0.39-0.29 (m, 1H). ¹⁹F NMR (376 MHz,Acetonitrile-d₃) δ −115.79-−115.91 (m). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₂₀H₁₇N₃O₄: 382.1; found: 382.1

Step 2 A solution of methyl2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetate(105.9 mg, 277.7 umol) in tetrahydrofuran (5 mL), methanol (5 mL) andwater (4 mL) was stirred at ambient temperature as 1 N lithium hydroxide(0.56 mL) was added. After 30 min, the reaction mixture was concentratedto remove most of the organic solvent, diluted with water, acidifiedwith 1 N hydrochloric acid, and the product was extracted with ethylacetate (×3). The combined extracts were dried with magnesium sulfate.After filtration, solvent was removed and dried in vacuum to give crude2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₉H₁₅FN₃O₄: 368.1; found:368.1

A solution of the crude2-((1aR,6aR)-3-((3-cyano-4-fluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid (18.02 mg, 49.06 umol),1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine (7.49 mg, 60.33 umol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (42.57 mg, 111.97 umol) inN,N-dimethylformamide (1 mL) was stirred at ambient temperature asN,N-diisopropylethylamine (0.07 mL, 401.9 umol) was added. After 30 min,the reaction mixture was diluted with ethyl acetate (30 mL), washed withaq. ammonium chloride (×2), aq. sodium bicarbonate (×2), and brine (×1).After the aq. fractions were extracted with ethyl acetate (×1), theorganic fractions were combined, dried with magnesium sulfate. Afterfiltration, solvent was removed and the residue was purified bypreparative HPLC (column, Gemini 10u C18 110A, AXI/; 250×21.2 mm)eluting 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide.

Example 80.(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(80)

Step 1 A solution of benzyl (1-ethynyl-3,3-difluorocyclobutyl)carbamate(291.4 mg, 1.099 mmol) and anisole (0.36 mL, 3.312 mmol) indichloromethane (4 mL) was stirred at 0° C. bath astrifluoromethanesulfonic acid (0.2 mL, 2.260 mmol) was added. After 2min, the mixture was stirred at ambient temperature for 2.25 h. Thereaction mixture was diluted with water (˜40 mL) and washed with amixture of ether and hexanes (1:3, 40 mL×1). The resulting aqueousfraction was concentrated using rotorvap and the residue wasco-evaporated with toluene (×2), dried in vacuum overnight, to get a 1:2mixture of 1-ethynyl-3,3-difluorocyclobutan-1-amine andtrifluoromethanesulfonic acid.

The mixture obtained above,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide (844.3 mg, 2.221 mmol), and(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid (230 mg, 0.923 mmol) were dissolved in N,N-dimethylformamide (5 mL)and stirred at 0° C. as N,N-diisopropylethylamine (1.6 mL, 9.185 mmol)was added. After 1 h at 0° C., the reaction mixture was diluted withethyl acetate (50 mL), washed with 10% aq. citric acid (×2), aq. sodiumbicarbonate (×2), and brine (×1). After the aq. fractions were extractedwith ethyl acetate (×1), the organic fractions were combined, dried withmagnesium sulfate. After filtration, solvent was removed and the residuewas purified by silica gel column chromatography eluting 0-90% ethylacetate in hexanes to give 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylate:¹H NMR (400 MHz, Chloroform-d) δ 8.76 (dd, J=4.5, 1.4 Hz, 1H), 8.46 (dd,J=8.4, 1.4 Hz, 1H), 7.49 (d, J=1.4 Hz, 1H), 7.48-7.45 (m, 1H), 4.48 (t,J=6.0 Hz, 1H), 3.65 (dd, J=19.3, 6.9 Hz, 1H), 3.40 (d, J=19.2 Hz, 1H),3.20 (h, J=13.5, 12.9 Hz, 4H), 2.76 (s, 3H), 2.53 (s, 1H), 2.14 (p,J=6.2 Hz, 1H), 1.17 (dt, J=8.6, 6.1 Hz, 1H), 0.54-0.39 (m, 1H). ¹⁹F NMR(376 MHz, Chloroform-d) δ −88.08-−89.18 (m, 1F), −91.67 (dp, J=200.1,11.6 Hz, 1F). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₁₉F₂N₆O₄:481.1; found: 480.9

Step 2-3(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamidewas synthesized from 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(1aR,6aR)-5-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylatein a manner similar to Example 56 using2-(difluoromethyl)-3-fluoropyridin-4-amine in place of2-(difluoromethyl)pyridin-4-amine.

Example 81(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(81) was synthesized in a manner similar to Example 79 using3,4-difluoroaniline in place of 5-amino-2-fluorobenzonitrile.

Example 82.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(82)

N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(82) was synthesized in a manner similar to Example 2 using2-amino-N,2-dimethylpropanamide hydrochloride in place ofR-trifluoroisopropylamine.

Example 83.6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(83) was synthesized in a manner similar to Example 82 using3,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 84.7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1. To a solution of methyl7-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(3.10 g, 11.1 mmol) in methanol (24 mL) was added 1 M lithium hydroxide(33.3 mL). After the resulting mixture was stirred at 65° C. for 3 h,the solution was concentrated to remove organic solvents, and theremained aqueous solution was diluted with water, acidified, and thenthe product was extracted with ethyl acetate. The extracts were driedover magnesium sulfate. After filtration, solvent was removed to give7-(carboxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid.

Step 2. A solution of7-(carboxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid (107 mg, 0.45 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (360 mg, 0.95 mmol) in dichloromethane (2mL) was stirred at as 1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-aminedihydrochloride (89 mg, 0.459 mmol) was added as a solution inN,N-dimethylformamide (0.5 mL) was added. After 4 h, the reactionmixture was treated with piperidine (0.2 mL) diluted with ethyl acetate(50 mL), washed with saturated aqueous ammonium chloride, saturatedsodium bicarbonate (×2), and brine (×1). After the aqueous fractionswere extracted with ethyl acetate (×1), the organic fractions werecombined, dried over magnesium sulfate. After filtration, solvent wasremoved under reduced pressure to afford product which was carried on ascrude, 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate:LCMS-ESI+ (n/z): [M+H]⁺ calculated for C₂₁H₂₀N₉O₄: 462.16; found: 461.9.

Step 3. To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate(104 mg, 0.23 mmol) and 3-chloro-2,4-difluoroaniline (74 mg, 0.45 mmol)in dichloromethane (3 mL) was added 2,6-lutidine (0.1 mL, 0.86 mmol) andthe resulting mixture was concentrated to an oil. The resulting oil washeated at 80° C. bath for 3 h. The residue was dissolved indichloromethane and the insoluble material was filtered off. After theconcentration of the filtrate, the residue was purified by reverse phasepreparative HPLC (10-100% acetonitrile in water, 0.1% trifluoroaceticacid) to give7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.

Example 85.7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(3-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(3-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(85) was synthesized in a manner similar to Example 84 using3-(trifluoromethoxy)aniline in place of 3-chloro-2,4-difluoroaniline.

Example 86.7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(5-chloro-2-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(5-chloro-2-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(86) was synthesized in a manner similar to Example 84 using5-chloro-2-fluoroaniline in place of 3-chloro-2,4-difluoroaniline.

Example 87(1aR,6aR)-5-(2-((3-(1H-1,2,3-triazol-4-yl)oxetan-3-yl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

Step 1 CuTC (15 mg, 0.079 mmol) followed by azidomethyl pivalate (122μL, 0.795 mmol) were added to a solution of theN-(3-ethynyloxetan-3-yl)-2-methylpropane-2-sulfinamide (160 mg, 0.795mmol) in THF (2 mL). After 1 h, a green solution formed. The solvent wasremoved under reduced pressure and the residue was purified byCombiFlash (12 g, Gold, 20-100% EtOAc/Hex) to give(S)-(4-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)-1H-1,2,3-triazol-1-yl)methylpivolate. ¹H NMR (400 MHz, Chloroform-d) δ 8.00 (s, 1H), 6.24 (s, 2H),5.15-5.06 (m, 2H), 4.97 (dd, J=14.6, 6.7 Hz, 2H), 4.37 (s, 1H), 1.28 (s,9H), 1.20 (s, 9H); LCMS-ESI+: calc'd for C₁₅H₂₇N₄O₄S: 359.18 [M+H]+;found: 358.93.

Step 2 To a solution of(4-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)-1H-1,2,3-triazol-1-yl)methylpivalate (53 mg, 0.148 mmol) in methanol (0.5 mL) at 0° C. was addeddropwise, down the side of the flask, HCl in dioxane (4N, 0.22 mL, 0.22mmol). Reaction mixture was stirred for 1 minute, and then concentrated.Ethyl ether (1 mL) was added to give a white solid and the mixture wasconcentrated. Ethyl ether (1.5 mL) was added, the resulting white solidwas collected by filtration, dried under high vacuum for 5 minutes, thenused in next step immediately.

Step 3 The crude (4-(3-aminooxetan-3-yl)-1H-1,2,3-triazol-1-yl)methylpivalate hydrochloride (14 mg, 0.048 mmol) was dissolved in DMF (0.5 mL)and N,N-Diisopropylethylamine (27 μL, 0.153 mmol) was added, followed by2-((1aR,6aR)-3-((3,4-difluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid (10 mg, 0.028 mmol), then HATU (16 mg, 0.042 mmol). Reactionmixture was stirred for 10 minutes, diluted with ethyl acetate andwashed with 5% lithium chloride solution, saturated sodium bicarbonatesolution, brine. The organic layer was dried (Na₂SO₄), filtered,concentrated and purified by CombiFlash (4 g, Gold, 0-100% EtOAc/Hex) togive(4-(3-(2-((1aR,6aR)-3-((3,4-difluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetamido)oxetan-3-yl)-1H-1,2,3-triazol-1-yl)methylpivalate: ¹H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.74 (ddd,J=12.7, 7.3, 2.5 Hz, 1H), 7.37-7.30 (m, 1H), 7.28-7.18 (m, 1H), 6.32 (s,2H), 5.05 (q, J=3.3, 2.4 Hz, 4H), 4.26 (t, J=5.8 Hz, 1H), 3.21 (dd,J=18.4, 6.7 Hz, 1H), 3.01 (d, J=18.7 Hz, 1H), 2.48 (s, 3H), 2.16-2.06(m, 1H), 1.18 (s, 9H), 1.08 (dt, J=8.6, 6.0 Hz, 1H), 0.89 (d, J=6.7 Hz,1H), 0.24 (td, J=5.7, 2.1 Hz, 1H); LCMS-ESI+ (m/z): [M+H]⁺ calculatedfor C₂₉H₃₁F₂N₆O₆: 597.2; found: 597.2

Step 4 To a solution of(4-(3-(2-((1aR,6aR)-3-((3,4-difluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoacetamido)oxetan-3-yl)-1H-1,2,3-triazol-1-yl)methylpivalate (9 mg, 0.015 mmol) in methanol (1.5 mL) was added 2M sodiumhydroxide (17 μL, 0.034 mmol) and reaction mixture was stirred for 1.5hours. LCMS showed full conversion. Reaction was quenched with 1N HCl(34 μL, 0.034 mmol), diluted with dichloromethane, adsorbed onto silicagel and purified by CombiFlash (4 g, Gold, 0-100% (20% MeOH/EtOAc)/Hex)to give(1aR,6aR)-5-(2-((3-(1H-1,2,3-triazol-4-yl)oxetan-3-yl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide.

Example 887-(2-((3-(1H-1,2,3-triazol-4-yl)oxetan-3-yl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3-(1H-1,2,3-triazol-4-yl)oxetan-3-yl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(88) was prepared in a similar manner to Example 87 except using2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid instead of2-((1aR,6aR)-3-((3,4-difluorophenyl)carbamoyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizin-5-yl)-2-oxoaceticacid.

Example 89.7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(89) was synthesized in a manner similar to Example 29 using3-(difluoromethyl)-4-fluoroaniline in place of3-chloro-4-fluouroaniline.

Example 90.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(90) was synthesized in a manner similar to Example 29 using1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid inplace of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine and2,4,5-trifluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 91.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(5-chloro-2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(5-chloro-2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(91) was synthesized in a manner similar to Example 90 using5-chloro-2,4-difluoroaniline in place of 2,4,5-trifluoroaniline.

Example 92.7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(92) was synthesized in a manner similar to Example 26 Step 4 using1-ethynylcyclopropan-1-amine hydrochloride in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 93.7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(93)

7-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(2,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(93) was synthesized in a manner similar to Example 84 using2,4-difluoroaniline in place of 3-chloro-2,4-difluoroaniline.

Example 94.N-(3-chloro-4-fluorophenyl)-7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((1-ethynylcyclopropyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(94) was synthesized in a manner similar to Example 6 Step 6 using1-ethynylcyclopropan-1-amine hydrochloride in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 95.(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(95) was synthesized in a manner similar to Example 5 using4-fluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 96.(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(96) was synthesized in a manner similar to Example 5 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 98:N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

A solution ofN-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)cyclopropyl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(97) (38.0 mg, 0.068 mmol) was treated with tetra n-butylammoniumfluoride (53.5 mg, 0.205 mmol) in tetrahydrofuran (2 mL) at rt for 1 h.The reaction mixture was directly injected into preparativereverse-phase HPLC (15-90% acetonitrile in water, 0.1% TFA buffer) toprovideN-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(98).

Example 99.(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(99)

(1aR,6aR)-5-(2-((1-(1H-1,2,3-triazol-5-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(99) was synthesized in a manner similar to Example 41 using1-(1H-1,2,3-triazol-5-yl)cyclopropan-1-amine in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine and4-fluoroaniline in place of 5-amino-2-fluorobenzonitrile.

Example 100.(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-5-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(100)

(1aR,6aR)-5-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-5-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluorophenyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(100) was synthesized in a manner similar to Example 41 using4-fluoroaniline in place of 5-amino-2-fluorobenzonitrile

Example 101.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-5-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-5-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3-chloro-5-fluoroaniline in place of 3-fluoroaniline.

Example 102.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,5-dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,5-dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3,5-dichloroaniline in place of 3-fluoroaniline.

Example 103.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)phenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)phenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3-(difluoromethyl)aniline in place of 3-fluoroaniline.

Example 104.N-(3-chloro-4-fluorophenyl)-7-(2-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(104) was synthesized in a manner similar to Example 29 using2-amino-2-methylpropane-1,3-diol in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine hydrochloride.

Example 105.N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(methylcarbamoyl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1 To a solution of1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (1.0 g,4.97 mmol), Methylamine hydrochloride (0.503 g, 7.45 mmol) andN,N-Diisopropylethylamine (3.46 mL, 19.9 mmol) in acetonitrile (50 mL)was added HATU (2.83 g, 7.45 mmol). Reaction mixture was stirred for 30minutes, concentrated, purified by CombiFlash to give tert-butyl(1-(methylcarbamoyl)cyclopropyl)carbamate. ¹H NMR (400 MHz, Methanol-d4)δ 2.82 (s, 3H), 2.74 (s, 3H), 1.44 (s, 9H), 1.40 (q, J=4.4 Hz, 2H),1.01-0.93 (m, 2H).

Step 2 To a solution of tert-butyl(1-(methylcarbamoyl)cyclopropyl)carbamate (94 mg, 0.44 mmol) in1,-4-dioxane (2 mL) was added 4N hydrogen chloride in 1,4-dioxane (0.5mL). Reaction mixture turned cloudy after 5 minutes. Reaction mixturewas stirred for 1 hour, then stored in freezer overnight. The mixturewas filtered and the white solid dried under house vacuum and used inthe next step without further purification.

Step 3 To a solution of2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (50 mg, 0.137 mmol), 1-amino-N-methylcyclopropane-1-carboxamidehydrochloride (25 mg, 0.164 mmol), and diisopropylethylamine (96 μL,0.55 mmol) was added HATU (78 mg, 0.206 mmol), Reaction mixture wasstirred for 30 minutes, then diluted with ethyl acetate, washed with 1NHCl, water, saturated sodium bicarbonate, 5% lithium chloride solution,brine and dried (Na₂SO₄), filtered and concentrated. The resultingresidue was dissolved in DMF, filtered through a syringe filter andpurified by Gilson HPLC (Gemini, 5-100% ACN/H₂O+0.1% TFA) andlyophilized to giveN-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((1-(methylcarbamoyl)cyclopropyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide.

3-aminobicyclo[1.1.1]pentane-1-carboxamide hydrochloride

Step 1. Isobutyl chloroformate (539 μL, 4.16 mmol) was added via syringeto a stirred mixture of N,N-diisopropylethylamine (773 μL, 4.44 mmol)and 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylicacid (630 mg, 2.77 mmol) in tetrahydrofuran (20 mL) at ambienttemperature. After 60 min, the resulting mixture was cooled to 0° C.Ammonia solution (0.4 M in tetrahydrofuran, 20.8 mL, 8.32 mmol) andN,N-diisopropylethylamine (773 μL, 4.44 mmol) were added sequentiallyvia syringe. After 15 min, the resulting mixture was warmed to ambienttemperature. After 80 min, the reaction mixture was purified by flashcolumn chromatography on silica gel (0 to 15% methanol indichloromethane) to give tert-butyl(3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate.

Step 2. Trifluoroacetic acid (10 mL) was added via syringe to a stirredsolution of tert-butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate(1.06 g, 4.67 mmol) in dichloromethane (10 mL) at ambient temperature.After 2 h, the resulting mixture was concentrated under reducedpressure, and the residue was dried azeotropically by concentrationunder reduced pressure from a mixture of 2-propanol and toluene (1:1v:v, 2×15 mL). The residue was dried azeotropically by concentrationunder reduced pressure from hydrogen chloride solution (5.0 M in2-propanol, 2×5 mL). The residue was dried azeotropically byconcentration under reduced pressure from a mixture of 2-propanol andtoluene (1:1 v:v, 15 mL) to give3-aminobicyclo[1.1.1]pentane-1-carboxamide hydrochloride.

Example 106.7-(2-((3-carbamoylbicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3-carbamoylbicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(106) was synthesized in a manner similar to Example 29 using3-aminobicyclo[1.1.1]pentane-1-carboxamide hydrochloride in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine hydrochloride.

3,3-difluoro-1-propionylcyclobutan-1-aminium chloride

Steps 1-2. Benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (3.30 g, 13.2mmol) was added as a solid to a stirred mixture of1-amino-3,3-difluorocyclobutane-1-carboxylic acid (2.00 g, 13.2 mmol)and N-ethyl-N-isopropylpropan-2-amine (4.61 mL, 26.5 mmol) inacetonitrile (40 mL) and water (20 mL) at ambient temperature. After 17h, diethyl ether (500 mL) was added. The organic layer was washed withaqueous hydrogen chloride solution (0.25 M, 2×300 mL) and water (500mL), was dried over anhydrous magnesium sulfate, was filtered, and wasconcentrated under reduced pressure. The residue was dissolved intoluene (90 mL) and methanol (27 mL), and the resulting solution wasstirred at ambient temperature. Diazomethyltrimethylsilane solution (2.0M in diethyl ether, 7.94 mL, 16 mmol) was added via syringe over 5 min.After 20 min, acetic acid was added dropwise via syringe until gasevolution ceased and the yellow color dissipated from the reactionmixture. The resulting mixture was concentrated under reduced pressure.The residue was purified by flash column chromatography (0 to 20% ethylacetate in hexanes) to give methyl1-(((benzyloxy)carbonyl)amino)-3,3-difluorocyclobutane-1-carboxylate.

Step 3. Ethylmagnesium bromide solution (1.0 M in tetrahydrofuran, 10.0mL, 10 mmol) was added over 5 min via syringe to a stirred mixture ofmethyl1-(((benzyloxy)carbonyl)amino)-3,3-difluorocyclobutane-1-carboxylate(1.00 g, 3.34 mmol) and tetraisopropoxytitanium (989 μL, 3.34 mmol) intetrahydrofuran (12 mL) at −65° C., and the reaction was allowed to warmto ambient temperature over 18 h. Saturated aqueous ammonium chloridesolution (20 mL) and diethyl ether (125 mL) were added. The organiclayer was washed sequentially with aqueous hydrogen chloride solution(0.5 M, 50 mL), saturated aqueous sodium bicarbonate solution (50 mL),and brine (25 mL), was dried over anhydrous magnesium sulfate, wasfiltered, and was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (0 to 20% ethylacetate in hexanes) to give benzyl(3,3-difluoro-1-propionylcyclobutyl)carbamate.

Step 4. A heterogeneous mixture benzyl(3,3-difluoro-1-propionylcyclobutyl)carbamate (291 mg, 0.979 mmol) andpalladium on activated carbon (10% wt/wt, 100 mg, 98 μmol) in ethanol(10 mL) at ambient temperature was placed under 1 atm of hydrogen gasand stirred vigorously. After 110 min, the reaction mixture was filteredthrough celite, and the filter cake was extracted with ethyl acetate (80mL). Hydrogen chloride solution (4 M in 1,4-dioxane, 0.30 mL) was addedvia syringe to the filtrate, and the resulting mixture was swirledvigorously for 1 min and then concentrated under reduced pressure togive 3,3-difluoro-1-propionylcyclobutan-1-aminium chloride.

Example 107.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-2-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-chloro-2-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3-chloro-2-fluoroaniline in place of 3-fluoroaniline.

Example 111.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(2,3,4-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(111)

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-6-methyl-N-(2,3,4-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(111) was synthesized in a manner similar to Example 90 using2,3,4-trifluoroaniline in place of 2,4,5-trifluoroaniline.

Example 112.N-(3-chloro-4-fluorophenyl)-7-(2-((3-cyanobicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Trifluoroacetic anhydride (28.6 μL, 0.206 mmol) was added via syringe toa stirred mixture of7-(2-((3-carbamoylbicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(32 mg, 0.069 mmol) and 2,6-lutidine (63.8 μL, 0.548 mmol) intetrahydrofuran (1.5 mL) at ambient temperature. After 10 min, water(0.5 mL) was added, and the resulting biphasic mixture was concentratedunder reduced pressure. The residue was purified by was purified byreverse phase preparative HPLC (10-100% acetonitrile in water, 0.1%trifluoroacetic acid) to giveN-(3-chloro-4-fluorophenyl)-7-(2-((3-cyanobicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(112).

Example 113.7-(2-((3-cyanobicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3-Cyanobicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(113) was synthesized in a manner similar to Example 112 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 114.N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(114)

N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-7-(2-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(114) was synthesized in a manner similar to Example 82 using3-(difluoromethyl)-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 115.7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)phenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)phenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 step 2 using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of 1-ethynylcyclopropan-1-amine 2,2,2-trifluoroacetate and in step3 using 3-(difluoromethyl)aniline in place of 3-fluoroaniline.

Example 116.7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 step 2 using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of 1-ethynylcyclopropan-1-amine 2,2,2-trifluoroacetate and in step3 using 3-(difluoromethyl)-4-fluoroaniline in place of 3-fluoroaniline.

Example 117.N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(117) was synthesized in a manner similar to Example 29 using(1-amino-3,3-difluorocyclobutyl)methanol hydrochloride in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine hydrochloride.

Example 118.7-(2-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(118) was synthesized in a manner similar to Example 29 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline and using(1-amino-3,3-difluorocyclobutyl)methanol hydrochloride in place of3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-amine hydrochloride.

Example 119.(1aR,6aR)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-5-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide

(1aR,6aR)-N-(2-(difluoromethyl)pyridin-4-yl)-4-methyl-5-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxamide(119) was synthesized from(1aR,6aR)-5-(carboxycarbonyl)-4-methyl-1,1a,6,6a-tetrahydrocyclopropa[b]pyrrolizine-3-carboxylicacid in a manner similar to Example 80, step 1 and 2 using3-(trifluoromethyl)oxetan-3-amine hydrochloride and2-(difluoromethyl)pyridin-4-amine in place of1-ethynyl-3,3-difluorocyclobutan-1-amine and2-(difluoromethyl)-3-fluoropyridin-4-amine, respectively.

Example 120.7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(120)

7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(120) was synthesized in a manner similar to Example 3 using1-amino-3,3-difluorocyclobutane-1-carboxamide hydrochloride in place of3,3-difluoro-(1-methylaminocarbonyl)-1-cyclobutanamine hydrochloride.

Synthesis of 1-amino-3,3-difluorocyclobutane-1-carboxamide hydrochloride

Step 1. To a 0° C. solution of1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid(522 mg, 2.1 mmol), ammonium chloride (620 mg, 11.6 mmol), andtriethylamine (2.3 mL, 16.5 mmol) in N,N-dimethylformamide (6 mL) wasadded 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.19 g, 3.12 mmol). The reaction was warmedto ambient temperature and stirred for 5 h, at which point the reactionmixture was diluted with diethyl ether, washed with a saturate aqueoussolution of sodium bicarbonate, a 5% aqueous solution of lithiumchloride, and brine. The ethereal phase was then dried over sodiumsulfate, filtered, and concentrated under reduced pressure to affordtert-butyl (1-carbamoyl-3,3-difluorocyclobutyl)carbamate which wascarried forward without further purification.

Step 2. Tert-butyl (1-carbamoyl-3,3-difluorocyclobutyl)carbamate (348mg, 1.39 mmol) was dissolved in a 4M solution of hydrogen chloride indioxane (6 mL, 24 mmol) and stirred at room temperature for 60 minutes.Solvent was removed under reduced pressure, twice azeotroping withtoluene, and the resultant material dried under high vacuum to afford1-amino-3,3-difluorocyclobutane-1-carboxamide hydrochloride: ¹H NMR (400MHz, DMSO-d6) δ 8.95 (s, 3H), 7.90 (s, 2H), 3.28 (td, J=13.0, 7.2 Hz,2H), 3.05 (q, J=14.2 Hz, 2H).

Example 121.7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(121)

7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(121) was synthesized in a manner similar to Example 120 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

1-amino-3,3-difluoro-N,N-dimethylcyclobutane-1-carboxamide hydrochloride

Step 1.1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine3-oxide hexafluorophosphate(V) (1.33 g, 3.51 mmol) was added to astirred mixture of1-(((benzyloxy)carbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid(1.00 g, 3.51 mmol), N,N-diisopropylethylamine (2.44 mL, 14.0 mmol),N,N-dimethylpyridin-4-amine (43 mg, 0.035 mmol), and dimethylaminehydrochloride (715 mg, 8.76 mmol) in N,N-dimethylformamide (10 mL) atambient temperature. After 90 min, diethyl ether (250 mL) was added. Theorganic layer was washed sequentially with aqueous hydrogen chloridesolution (0.2 M, 2×200 mL), a mixture of saturated aqueous sodiumbicarbonate solution and water (1:4 v:v, 200 mL), and water (200 mL),was dried over anhydrous magnesium sulfate, was filtered, and wasconcentrated under reduced pressure to give benzyl(1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)carbamate.

Step 2. A heterogeneous mixture of benzyl(1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)carbamate (645 mg, 2.07mmol) and palladium on activated carbon (10% wt/wt, 220 mg, 0.207 μmol)in ethanol (10 mL) and ethyl acetate (5.0 mL) at ambient temperature wasplaced under 1 atm of hydrogen gas and stirred vigorously. After 3.5 h,the reaction mixture was filtered through celite, and the filter cakewas extracted with ethyl acetate (80 mL). Hydrogen chloride solution (4M in 1,4-dioxane, 2.0 mL) was added via syringe to the filtrate, and theresulting mixture was swirled vigorously for 1 min and then concentratedunder reduced pressure to give1-amino-3,3-difluoro-N,N-dimethylcyclobutane-1-carboxamidehydrochloride.

Example 124.N-(3-chloro-4-fluorophenyl)-7-(2-((1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4-fluorophenyl)-7-(2-((1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(124) was synthesized in a manner similar to Example 29 using1-amino-3,3-difluoro-N,N-dimethylcyclobutane-1-carboxamide hydrochloridein place of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 125.N-(3,4-difluorophenyl)-7-(2-((1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3,4-difluorophenyl)-7-(2-((1-(dimethylcarbamoyl)-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(125) was synthesized in a manner similar to Example 29 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline and using1-amino-3,3-difluoro-N,N-dimethylcyclobutane-1-carboxamide hydrochloridein place of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 126.7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-5-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-(1H-1,2,3-triazol-4-yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3-cyano-5-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 using3-fluoro-5-cyanoaniline in place of 3-fluoroaniline.

Example 127.N-(3-chloro-2,4-difluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(127)

N-(3-chloro-2,4-difluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(127) was synthesized in a manner similar to Example 3 using3-chloro-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.

Example 128.(S)—N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((3-methyl-1-(methylamino)-1-oxobutan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(128)

(S)—N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-((3-methyl-1-(methylamino)-1-oxobutan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(128) was synthesized in a manner similar to Example 84 using L-valineN-methylamide hydrochloride in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloride and3-chloro-4-fluoroaniline in place of 3-chloro-2,4-difluoroaniline.

Example 129.N-(3-chloro-4,5-difluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

N-(3-chloro-4,5-difluorophenyl)-7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 69 step 2 using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of 1-ethynylcyclopropan-1-amine 2,2,2-trifluoroacetate and in step3 using 3-chloro-4,5-difluoroaniline in place of 3-fluoroaniline.

Example 130.N-(3-chloro-4-fluorophenyl)-7-(2-((1-cyano-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Trifluoroacetic anhydride (23 μL, 0.16 mmol) was added via syringe to astirred mixture of7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(27 mg, 0.055 mmol) and 2,6-lutidine (51 μL, 0.44 mmol) intetrahydrofuran (1.0 mL) at ambient temperature. After 10 min, water(0.5 mL) was added, and the resulting biphasic mixture was stirredvigorously. After 5 min, the biphasic mixture was concentrated underreduced pressure. The residue was purified by was purified by reversephase preparative HPLC (10-100% acetonitrile in water, 0.1%trifluoroacetic acid) to giveN-(3-chloro-4-fluorophenyl)-7-(2-((1-cyano-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(130).

Example 131.7-(2-((1-cyano-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((1-cyano-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(131) was synthesizes in a manner similar to Example 130 using7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamidein place of7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.

Example 132.(R)—N-(3-Chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

(R)—N-(3-chloro-4-fluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(132) was synthesized in a manner similar to Example 29 using(R)-2-amino-3,3,3-trifluoro-2-methylpropan-1-ol hydrochloride in placeof 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 133.(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(133) was synthesized in a manner similar to Example 29 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline and using(R)-2-amino-3,3,3-trifluoro-2-methylpropan-1-ol hydrochloride in placeof 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 134:(R)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1(R)-7-(2-ethoxy-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid (0.83 g, 2.9 mmol) was taken up as a homogeneous mixture inTHF/MeOH/water (2:2:1, 15 mL) and treated at room temperature withlithium hydroxide monohydrate (0.31 g, 7.3 mmol) in a single portion.The mixture was sonicated to homogeneity. When LC/MS analysis indicatedthe completion of the reaction, the mixture was diluted with ice (˜10 g)and treated dropwise with 20% aqueous sulfuric acid to pH 1. Afterextraction three three times with ethyl acetate, the combined organicswere washed once with saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and concentrated to provide(R)-7-(carboxycarbonyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₁H₁₁FNO₅: 256.1; found:255.9

Step 21-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 2.4 g, 6.3 mmol) was added in a singleportion to a mixture of((R)-7-(carboxycarbonyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylicacid (0.77 g, 3.0 mmol), 1-ethynyl-3,3-difluorocyclobutan-1-aminebistriflate (1.6 g, 3.8 mmol), and N,N-diisopropylethylamine (5.0 mL, 29mmol) in N,N-dimethylformamide (15 mL). When LC/MS analysis confirmedthe sufficient completion of the reaction, the mixture was partitionedbetween ethyl acetate and saturated aqueous sodium hydrogen carbonatesolution. The aqueous phase was extracted three times with ethylacetate. The combined extracts were washed with a mixture of saturatedaqueous sodium chloride/saturated aqueous sodium hydrogen carbonatesolutions (˜5:1), dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure.

The residue was purified by flash chromatography (silica gel) to provide3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₂H₁₈F₃N₆O₄: 487.1; found: 487.9

Step 3 To a suspension of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate,(0.48 g, 0.99 mmol) and 2-(difluoromethyl)-3-fluoropyridin-4-aminehydrochloride (0.59 g, 3.0 mmol) in dichloromethane (10 mL) was added2,6-lutidine (0.70 mL, 5.9 mmol). The resulting mixture was concentratedon the rotary evaporator to give a suspension. It was taken up again indichloromethane (10 mL) and concentrated to a homogeneous residue, whichwas then heated at 100° C. for seven days.

After cooling, the residue was purified by flash chromatography (silicagel) to provide(R)—N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₁₉F₆N₄O₃: 513.1; found: 513.2

Step 4 A mixture of(R)—N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(0.16 g, 0.31 mmol) in N,N-dimethylformamide/methanol (9:1 mixture, 6mL) was stirred in an ice-water bath while being degassed with Argon for10 minutes. To the solution was then added copper(I)thiophene-2-carboxylate (30 mg, 0.16 mmol) and the resulting mixture wasfurther subjected to Argon for 10 minutes. Azidotrimethylsilane (210 μL,1.6 mmol) was added to the mixture. The vial was sealed and the mixturewas stirred overnight at 100° C.

After cooling to room temperature, the reaction mixture wasconcentrated, and the residue was purified by preparative reverse-phaseHPLC (10-80% acetonitrile in water, 0.1% TFA buffer) to provide(R)-7-(2-((3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₃H₂₀F₆N₇O₃: 556.2; found: 556.2

(R)-2-(2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetamido)-3,3,3-trifluoro-2-methylpropanoicacid

(R)-2-(2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetamido)-3,3,3-trifluoro-2-methylpropanoicacid was synthesized in a manner similar to Example 29 using3,4-difluoroaniline in place of 3-chloro-4-fluoroaniline and using(R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride inplace of 3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutan-1-aminehydrochloride.

Example 135.(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

1-((Dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine3-oxide hexafluorophosphate(V) (35 mg, 0.092 mmol) was added to astirred mixture of(R)-2-(2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoacetamido)-3,3,3-trifluoro-2-methylpropanoicacid (15 mg, 0.031 mmol), ammonium chloride (8.2 mg, 0.15 mmol),N,N-dimethylpyridin-4-amine (3.8 mg, 0.031 mmol), and 1-methylmorpholine(40.6 μL, 0.369 mmol) in N,N-dimethylformamide (1.5 mL) at ambienttemperature. After 120 min, the residue was purified by was purified byreverse phase preparative HPLC (10-100% acetonitrile in water, 0.1%trifluoroacetic acid) to give(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(135).

Example 136.(S)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

(S)-7-(2-((3-amino-1,1,1-trifluoro-2-methyl-3-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamideacid (136) was synthesized in a manner similar to Example 135 using(S)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride inplace of (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acidhydrochloride.

Example 137.(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methyl-3-(methylamino)-3-oxopropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

(R)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methyl-3-(methylamino)-3-oxopropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(137) was synthesized in a manner similar to Example 135 usingmethylamine hydrochloride in place of ammonium chloride.

Example 138.(S)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methyl-3-(methylamino)-3-oxopropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

(S)—N-(3,4-difluorophenyl)-6-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methyl-3-(methylamino)-3-oxopropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(138) was synthesized in a manner similar to Example 135 usingmethylamine hydrochloride in place of ammonium chloride and using(S)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride inplace of (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acidhydrochloride.

Example 140.7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(140)

7-(2-((1-carbamoyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-6-methyl-N-(3,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(140) was synthesized in a manner similar to Example 26 Step 4 using1-amino-3,3-difluorocyclobutane-1-carboxamide in place of1-(1H-1,2,3-triazol-4-yl)cyclopropan-1-amine dihydrochloric acid.

Example 145.N-(3,4-difluorophenyl)-6-methyl-7-(2-((3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1 A mixture of 3-methylthietan-3-amine hydrochloride (93 mg, 0.67mmol) and2-(5-((3,4-difluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolizin-7-yl)-2-oxoaceticacid (0.20 g, 0.58 mmol) was taken up in N,N-dimethylformamide andtreated successively with N,N-diisopropylethylamine (0.51 mL, 2.9 mmol)and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 0.29 g, 0.75 mmol). After 4 hours ofstirring, the mixture was partitioned between ethyl acetate andsaturated aqueous sodium hydrogen carbonate solution. The aqueous phasewas extracted three times with ethyl acetate. The combined organicphases were subsequently washed successively with ˜5% aqueoushydrochloric acid, half-saturated aqueous sodium chloride solution, anda 1:1 mixture of saturated aqueous sodium hydrogen carbonate and sodiumchloride solutions. The organics were then dried over anhydrousmagnesium sulfate, filtered, concentrated, and concentrated to provideN-(3,4-difluorophenyl)-6-methyl-7-(2-((3-methylthietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₁H₂₂F₂N₃O₃S: 434.1; found:434.2

Step 2 A suspension ofN-(3,4-difluorophenyl)-6-methyl-7-(2-((3-methylthietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide(0.25 g, 0.58 mmol) was taken up as a suspension in acetonitrile (4 mL)was heated to homogeneity. After cooling, the cloudy mixture was treatedwith iron(III) chloride (4.7 mg, 0.03 mmol). After five minutes ofstirring, periodic acid (hydrated, 0.15 g, 0.64 mmol) was added in asingle portion.

After LC/MS analysis confirmed the complete consumption of startingmaterial, the mixture was quenched by the addition of 25% wt/wt aqueoussodium thiosulfate solution (2 mL). The suspension was allowed to stirfor 10 minutes, was diluted with water, and then was extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate and filtered. The still biphasic filtrate was poured intoseparatory funnel. The remaining aqueous layer was removed. The organicswere then dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure.

The residue was purified by preparative reverse-phase HPLC (5-60%acetonitrile in water, 0.1% TFA buffer) to provideN-(3,4-difluorophenyl)-6-methyl-7-(2-((3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamideas an approximately 2:1 mixture of diastereomers. LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₂₁H₂₂F₂N₃O₄S: 450.1; found: 450.2

Example 147.7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide

7-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide(147) was synthesized in a manner similar to Example 2 using1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride inplace of), R-trifluoroisopropylamine, and2-(difluoromethyl)-3-fluoropyridin-4-amine hydrochloride in place of3-chloro-4-fluoroaniline

Example 150.(R)—N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-2-fluoro-6-methyl-7-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-2-fluoro-6-methyl-7-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxylatewas prepared in analogous fashion to3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl(R)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate,using 3-(trifluoromethyl)oxetan-3-amine hydrochloride in place of1-ethynyl-3,3-difluorocyclobutan-1-amine bistriflate. LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₂₀H₁₇F₄N₆O₅: 497.1; found: 496.9

Step 2(R)—N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-2-fluoro-6-methyl-7-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas prepared in analogous fashion to(R)—N-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-7-(2-((1-ethynyl-3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-2-fluoro-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide.LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₁H₁₈F₇N₄O₄: 523.1; found: 523.2

Example 151.N-(3,4-difluorophenyl)-6-methyl-7-(2-(((1r,3r)-3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1 N,N-diisopropylethylamine (2.0 mL, 11 mmol) and N-Cbz succinimide(1.3 g, 5.2 mmol) were added successively to a solution of3-methylthietan-3-amine hydrochloride (0.72 g, 5.2 mol) indichloromethane (15 mL) at room temperature. After remaining overnightat room temperature, the mixture was diluted with diethyl ether (60 mL)and washed successively with 10% aqueous hydrochloric acid (50 mL×2) andsaturated aqueous sodium chloride solution. The organic phase was driedover anhydrous magnesium sulfate, filtered, and concentrated to givebenzyl (3-methylthietan-3-yl)carbamate. LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₂H₁₆NO₂S: 238.1; found: 238.0

Step 2 A solution of benzyl (3-methylthietan-3-yl)carbamate (1.2 g, 5.2mmol) in acetonitrile (5 mL) was treated with iron(I) chloride (42 mg,0.26 mmol), and the resulting mixture was stirred for about 5 minutes atroom temperature before the addition of periodic acid (hydrated, 1.3 g,5.7 mmol). After about 2 hours of stirring, the mixture was quenched bythe addition of 25% wt/wt aqueous sodium thiosulfate solution (Na₂S₂O₃,˜2 mL). The ensuing suspension was stirred for 10 minutes and thenfiltered through a pad of Celite diatomaceous earth. The filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand extracted with dichloromethane three times. The aqueous phase wassaturated with sodium chloride and subsequently extracted three moretimes each with dichloromethane and ethyl acetate. The combined organicswere dried organics over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel) to provide two diastereomers, arbitrarilyassigned cis and trans conformations.

Diasteromer 1 (first to elute from silica gel): benzyl((1r,3r)-3-methyl-1-oxidothietan-3-yl)carbamate

Diasteromer 2: benzyl ((1s,3s)-3-methyl-1-oxidothietan-3-yl)carbamate

LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₁₂H₁₆NO₃S: 254.1; found: 254.1

Step 3 A solution benzyl ((1r,3r)-3-methyl-1-oxidothietan-3-yl)carbamate(0.23 g, 0.79 mmol) and anisole (290 μL, 2.7 mmol) in dichloromethane (5mL) was cooled in an ice-water bath. Trifluoromethanesulfonic acid (160μL, 1.8 mmol) was added dropwise. The cooling bath was removed, and themixture was allowed to warm to ambient temperature.

After one hour, the mixture was diluted with water and was extractedonce with diethyl ether/hexane (1:3, 20 mL). The aqueous layer wasconcentrated to provide (1r,3r)-3-amino-3-methylthietane 1-oxidebistriflate. LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₄H₁₀NOS: 120.0;found: 119.8

Step 4N-(3,4-difluorophenyl)-6-methyl-7-(2-(((1r,3r)-3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas prepared in analogous fashion toN-(3,4-difluorophenyl)-7-(2-((3-(dimethylphosphoryl)oxetan-3-yl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-5-carboxamideusing (1r,3r)-3-amino-3-methylthietane 1-oxide bistriflate in place of(3-aminooxetan-3-yl)dimethylphosphine oxide hydrochloride and purifyingby flash chromatography (silica gel) instead of preparativereverse-phase HPLC. LCMS-ESI+ (m/z): [M+H]⁺ calculated forC₂₁H₂₂F₂N₃O₄S: 450.1; found: 450.2

Example 152.N-(3,4-difluorophenyl)-6-methyl-7-(2-(((1s,3s)-3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide

Step 1 Benzyl ((1s,3s)-3-methyl-1-oxidothietan-3-yl)carbamate wasisolated via the flash chromatography that also provided benzyl((1r,3r)-3-methyl-1-oxidothietan-3-yl)carbamate LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₂H₁₆NO₃S: 254.1; found: 254.1

Step 2 (1s,3s)-3-amino-3-methylthietane 1-oxide bistriflate was derivedfrom benzyl ((1s,3s)-3-methyl-1-oxidothietan-3-yl)carbamate in a mannersimilar to that which furnished (1r,3r)-3-amino-3-methylthietane 1-oxidebistriflate

Step 3N-(3,4-difluorophenyl)-6-methyl-7-(2-(((1s,3s)-3-methyl-1-oxidothietan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamidewas synthesized in a manner similar to Example 151, using(1s,3s)-3-amino-3-methylthietane 1-oxide bistriflate in place of(1r,3r)-3-amino-3-methylthietane 1-oxide bistriflate and by purifyingfirst via flash chromatography (silica gel) and then by preparativereverse-phase HPLC (10-70% acetonitrile in water, 0.1% TFA buffer).LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₂₁H₂₂F₂N₃O₄S: 450.1; found:450.2

Analytical Data for compounds 1 to 49 are set forth in the table below.Additionally, analytical data for compounds 50 to 152 are set forth inthe table below.

Compound ES/MS # m/z ¹H-NMR 1 430.9  1H NMR (400 MHz, Chloroform-d) δ8.79 (s, 1H), 8.07 (dd, J = 5.5, 2.7 Hz, 1H), 7.71 (ddd, J = 9.1, 4.5,2.8 Hz, 1H), 7.23-7.15 (m, 1H), 6.83 (s, 1H), 4.54-4.43 (m, 2H), 3.29(t, J = 7.6 Hz, 2H), 2.48 (p, J = 7.6 Hz, 2H), 1.44 (s, 9H). 2 460.2  1HNMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.27 (d, J = 8.8 Hz, 1H), 7.93(dd, J = 6.9, 2.6 Hz, 1H), 7.58 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.38(t, J = 9.1 Hz, 1H), 4.68 (dq, J = 15.3, 7.6 Hz, 1H), 4.13 (t, J = 7.3Hz, 2H), 2.96-2.78 (m, 2H), 2.42 (s, 5H), 1.30 (d, J = 7.0 Hz, 3H). 3511.4  1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.42 (s, 1H), 7.94 (dd,J = 6.8, 2.6 Hz, 1H), 7.78 (t, J = 4.5 Hz, 1H), 7.58 (ddd, J = 9.0, 4.3,2.6 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 4.13 (t, J = 7.3 Hz, 2H), 3.20(td, J = 14.8, 11.7 Hz, 2H), 3.01-2.79 (m, 4H), 2.59 (d, J = 4.6 Hz,3H), 2.46-2.31 (m, 5H). 4 523.0  1H NMR (400 MHz, DMSO-d6) δ 10.09 (s,1H), 9.41 (s, 1H), 7.97 (dd, J = 6.9, 2.6 Hz, 1H), 7.80 (d, J = 4.8 Hz,1H), 7.61 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H),4.23 (t, J = 5.9 Hz, 1H), 3.32-2.77 (m, 5H), 2.60 (d, J = 4.5 Hz, 3H),2.40 (s, 3H), 2.10 (t, J = 7.1 Hz, 1H), 1.05 (dt, J = 8.4, 5.7 Hz, 1H),0.14 (dt, J = 5.9, 3.0 Hz, 1H). 5 522.9  1H NMR (400 MHz, DMSO-d6) δ10.09 (s, 1H), 9.41 (s, 1H), 7.97 (dd, J = 6.9, 2.6 Hz, 1H), 7.80 (d, J= 4.8 Hz, 1H), 7.61 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.39 (t, J = 9.1Hz, 1H), 4.23 (s, 1H), 3.29-2.76 (m, 2H), 2.60 (d, J = 4.5 Hz, 3H), 2.40(s, 3H), 1.05 (dd, J = 8.5, 5.7 Hz, 1H), 0.13 (s, 1H). 6 471.1  1H NMR(400 MHz, Methanol-d4) δ 7.88 (dd, J = 6.7, 2.6 Hz, 1H), 7.72 (s, 1H),7.51 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 4.20 (t,J = 7.3 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 2.47 (p, J =7.4 Hz, 2H), 1.49-1.28 (m, 4H). 7 488.0  1H NMR (400 MHz, DMSO-d6) δ10.01 (s, 1H), 9.81 (s, 1H), 7.95 (dd, J = 6.8, 2.6 Hz, 1H), 7.59 (ddd,J = 9.3, 4.3, 2.6 Hz, 1H), 7.40 (t, J = 9.1 Hz, 1H), 4.83 (d, J = 9.1Hz, 2H), 4.76 (d, J = 8.3 Hz, 2H), 4.22-4.08 (m, 2H), 2.97 (t, J = 7.7Hz, 2H), 2.45 (d, J = 2.8 Hz, 5H). 8 579.1  1H NMR (400 MHz,Methanol-d4) δ 7.88 (dd, J = 6.7, 2.6 Hz, 1H), 7.52 (dq, J = 9.0, 3.0Hz, 1H), 7.23 (t, J = 9.0 Hz, 1H), 4.79 (d, J = 7.0 Hz, 2H), 4.76 (d, J= 7.0 Hz, 2H), 4.54 (s, 2H), 4.22 (t, J = 7.3 Hz, 2H), 4.18 (s, 2H),3.52-3.33 (m, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.88 (td, J = 14.3, 6.3 Hz,2H), 2.55 (s, 3H), 2.54-2.46 (m, 2H). 9 656.1  1H NMR (400 MHz, DMSO-d6)δ 10.02 (br s, 1H), 9.71 (br s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H),7.60 (ddd, J = 9.2, 4.3, 2.4 Hz, 1H), 7.41 (t, J = 9.1 Hz, 1H), 4.30 (s,2H), 4.16 (t, J = 7.2 Hz, 2H), 4.06 (s, 2H), 4.05-3.95 (m, 4H), 3.44 (t,J = 7.4 Hz, 2H), 2.98 (s, 3H), 2.89 (t, J = 7.4 Hz, 4H), 2.45 (s, 3H),2.44- 2.38 (m, 2H). 10 565.1  1H NMR (400 MHz, Methanol-d4) δ 7.88 (dd,J = 6.7, 2.6 Hz, 1H), 7.56-7.48 (m, 1H), 7.23 (t, J = 9.0 Hz, 1H),4.87-4.65 (m, 2H), 4.60-4.35 (s, 2H), 4.23 (t, J = 7.3 Hz, 2H), 3.73 (s,2H), 3.11 (t, J = 7.6 Hz, 2H), 3.04- 2.92 (m, 4H), 2.54 (s, 3H),2.57-2.45 (m, 2H). 11 579.1  1H NMR (400 MHz, Methanol-d4) δ 7.88 (dd, J= 5.3, 3.1 Hz, 1H),7.51 (dd, J = 8.9, 4.5 Hz, 1H), 7.23 (td, J = 9.0,1.4 Hz, 1H), 5.40 (d, J = 6.8 Hz, 2H), 4.63 (d, J = 6.9 Hz, 2H), 4.19(dt, J = 26.2, 7.3 Hz, 4H), 3.44 (q, J = 13.9 Hz, 2H), 3.03 (t, J = 7.5Hz, 2H), 2.88 (td, J = 14.1, 6.6 Hz, 2H), 2.64-2.45 (m, 9H) 12 488.1  1HNMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.88 (s, 1H), 9.42 (s, 1H), 7.96(dd, J = 6.8, 2.4 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 9.1Hz, 1H), 4.15 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.45 (s,3H), 2.38-2.44 (m, 2H), 1.70-1.64 (m, 2H), 1.49- 1.43 (m, 2H). 13 627.1 1H NMR (400 MHz, DMSO-d6) δ 10.03 (br s, 1H), 9.73 (br s, 1H), 7.96 (dd,J = 6.8, 2.5 Hz, 1H), 7.67-7.55 (m, 1H), 7.41 (t, J = 9.1 Hz, 1H), 4.47(d, J = 13.5 Hz, 2H), 4.40 (s, 2H), 4.38 (d, J = 13.5 Hz, 2H), 4.24-4.05(m, 4H), 2.90 (quin, J = 7.3 Hz, 4H), 2.45 (s, 3H), 2.42 (d, J = 7.4 Hz,2H). 14 555.1  1H NMR (400 MHz, DMSO-d6) δ 10.03 (br s, 1H), 9.74 br (s,1H), 7.90-7.95 (m, 1H), 7.50-7.65 (m, 1H), 7.30-7.45 (m, 1H), 5.20- 5.45(m, 1H), 4.00-4.60 (m, 6H), 2.83-2.87 (m, 2H), 2.70-2.80 (m, 2H), 2.44(s, 3H). 15 539.0  1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.41 (s,1H), 7.98 (dd, J = 6.9, 2.6 Hz, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.60(ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H), 3.20 (q, J =14.5 Hz, 2H), 2.91 (dt, J = 23.1, 7.0 Hz, 4H), 2.59 (d, J = 4.6 Hz, 3H),2.32 (s, 3H), 2.24 (t, J = 7.2 Hz, 2H), 1.50 (s, 6H). 16 527.0  1H NMR(400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.41 (s, 1H), 7.93 (dd, J = 6.8, 2.6Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.58 (ddd, J = 9.0, 4.2, 2.5 Hz, 1H),7.38 (t, J = 9.1 Hz, 1H), 4.73 (s, 1H), 4.26 (dd, J = 12.4, 5.4 Hz, 1H),3.96 (dd, J = 12.4, 2.1 Hz, 1H), 3.23-3.12 (m, 3H), 3.01-2.80 (m, 3H),2.60 (d, J = 4.6 Hz, 3H), 2.45 (s, 3H). 17 488.1  1H NMR (400 MHz,DMSO-d6) δ 10.43 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 6.8,2.6 Hz, 1H), 7.59 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz,1H), 4.75-4.60 (m, 1H), 2.89 (td, J = 7.2, 4.7 Hz, 2H), 2.29 (d, J =10.1 Hz, 5H), 1.50 (d, J = 2.1 Hz, 5H), 1.30 (d, J = 7.0 Hz, 3H). 18525.0  1H NMR (400 MHz, Acetone-d6) δ 9.18 (s, 1H), 8.63 (s, 1H),8.12-8.01 (m, 1H), 7.67 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.51-7.39 (m,1H), 7.29 (q, J = 9.2 Hz, 1H), 4.92 (t, J = 6.9 Hz, 1H), 3.31 (s, 6H),3.17-2.92 (m, 2H), 2.75 (d, J = 4.7 Hz, 3H), 2.52 (s, 3H), 1.30 (d, J =6.4 Hz, 3H). 19 516.0  1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.42(s, 1H), 8.15 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.2, 4.8, 2.7Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 4.79 (d, J= 6.5 Hz, 1H), 3.27-3.11 (m, 1H), 3.06-2.81 (m, 3H), 2.59 (d, J = 4.5Hz, 3H), 2.42 (s, 3H), 2.03 (d, J = 7.1 Hz, 1H), 1.19 (d, J = 6.4 Hz,3H). 20 474.2  1H NMR (400 MHz, Acetone-d6) δ 8.22- 8.00 (m, 1H), 7.67(dt, J = 9.1, 3.5 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 4.92 (t, J = 6.7Hz, 1H), 4.79 (p, J = 7.3 Hz, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.30 (s,1H), 3.15-2.99 (m, 5H), 2.80 (d, J = 13.3 Hz, 2H), 2.69 (dq, J = 12.8,8.9 Hz, 1H), 2.51 (d, J = 1.7 Hz, 3H), 2.22- 2.09 (m, 1H), 1.96 (s, 2H),1.46 (d, J = 7.1 Hz, 3H), 1.30 (dd, J = 6.4, 2.6 Hz, 3H), 1.20 (t, J =7.1 Hz, 2H). 21 482.1  1H NMR (400 MHz, Methanol-d4) δ 7.88 (dd, J =6.6, 2.6 Hz, 1H), 7.52 (dd, J = 8.4, 3.9 Hz, 1H), 7.23 (t, J = 9.0 Hz,1H), 4.55 (d, J = 14.4 Hz, 2H), 4.33-4.15 (m, 4H), 3.11 (t, J = 7.6 Hz,2H), 2.54 (s, 3H), 2.52 (d, J = 7.3 Hz, 2H), 1.81 (s, 3H). 22 525.2  1HNMR (400 MHz, Chloroform-d) δ 7.78 (dd, J = 6.5, 2.7 Hz, 1H), 7.59 (s,1H), 7.40- 7.33 (m, 2H), 7.13 (t, J = 8.7 Hz, 1H), 6.68 (s, 1H),5.10-4.98 (m, 1H), 3.52-3.36 (m, 2H), 3.19 (dd, J = 11.8, 5.5 Hz, 2H),2.95-2.81 (m, 5H), 2.64 (s, 4H), 1.38-1.35 (m, 4H), 1.25 (s, 4H). 23525.2  1H NMR (400 MHz, Chloroform-d) δ 7.78 (dd, J = 6.5, 2.6 Hz, 1H),7.60 (s, 1H), 7.41- 7.33 (m, 2H), 7.13 (t, J = 8.7 Hz, 1H), 6.68 (s,1H), 5.10-4.97 (m, 1H), 3.50-3.35 (m, 2H), 3.26-3.12 (m, 2H), 2.95-2.79(m, 5H), 2.63 (s, 4H), 1.36 (d, J = 6.4 Hz, 3H), 1.30-1.18 (m, 3H). 24474.3  1H NMR (400 MHz, Chloroform-d) δ 7.77 (dd, J = 6.5, 2.6 Hz, 1H),7.36 (ddd, J = 8.9, 4.0, 2.6 Hz, 2H), 7.13 (t, J = 8.7 Hz, 1H), 7.06 (d,J = 9.7 Hz, 1H), 5.02 (p, J = 6.8 Hz, 1H), 4.68 (dp, J = 9.7, 7.1 Hz,1H), 3.26 (dt, J = 18.1, 9.3 Hz, 1H), 3.13 (ddd, J = 17.9, 9.3, 2.0 Hz,1H), 2.65 (s, 4H), 2.19-2.07 (m, 1H), 1.42 (d, J = 7.0 Hz, 3H), 1.37 (d,J = 6.4 Hz, 3H). 25 474.3  1H NMR (400 MHz, Chloroform-d) δ 7.78 (dd, J= 6.5, 2.6 Hz, 1H), 7.39-7.32 (m, 2H), 7.16-7.06 (m, 2H), 5.03 (t, J =6.9 Hz, 1H), 4.68 (dt, J = 9.7, 7.0 Hz, 1H), 3.29 (ddd, J = 17.9, 9.6,2.6 Hz, 1H), 3.16 (dt, J = 17.8, 8.8 Hz, 1H), 2.63 (s, 4H), 2.17-2.07(m, 1H), 1.42 (d, J = 7.0 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H). 26 473.1 1H NMR (400 MHz, Methanol-d4) δ 7.71 (d, J = 1.0 Hz, 1H), 7.48 (dd, J =10.0, 6.3 Hz, 2H), 4.20 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H),2.51 (d, J = 1.0 Hz, 3H), 2.46 (quin, J = 7.4 Hz, 2H), 1.47-1.30 (m,4H). 27 615.1  1H NMR (400 MHz, Methanol-d4) δ 7.88 (dd, J = 6.7, 2.6Hz, 1H), 7.56-7.48 (m, 1H), 7.23 (t, J = 9.0 Hz, 1H), 4.43 (d, J = 14.1Hz, 2H), 4.22 (t, J = 7.3 Hz, 2H), 4.15 (d, J = 14.4 Hz, 2H), 3.44-3.32(m, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.97-2.79 (m, 2H), 2.55 (s, 3H),2.54-2.47 (m, 2H), 1.72 (s, 3H). 28 601.1  1H NMR (400 MHz, Methanol-d4)δ 7.88 (dd, J = 6.7, 2.5 Hz, 1H), 7.51 (ddd, J = 9.0, 4.2, 2.5 Hz, 1H),7.22 (t, J = 9.0 Hz, 1H), 4.27 (d, J = 14.4 Hz, 2H), 4.22 (t, J = 7.4Hz, 2H), 4.10 (d, J = 14.6 Hz, 2H), 3.24 (s, 2H), 3.12 (t, J = 7.5 Hz,2H), 3.07 (s, 2H), 2.96 (t, J = 12.1 Hz, 4H), 2.54 (s, 3H), 2.53-2.47(m, 2H), 1.69 (s, 3H). 29 521.1  1H NMR (400 MHz, Acetone-d6) δ 9.03 (s,1H), 8.68 (s, 1H), 8.05 (dd, J = 6.8, 2.6 Hz, 1H), 7.84 (s, 1H),7.74-7.56 (m, 1H), 7.29 (t, J = 9.0 Hz, 1H), 4.25 (t, J = 7.3 Hz, 2H),3.48-3.33 (m, 4H), 3.00 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 2.46 (p, J =7.5 Hz, 2H). 30 514.2  1H NMR (400 MHz, Acetonitrile-d3) δ 8.39 (s, 1H),8.09 (dd, J = 5.7, 2.7 Hz, 1H), 8.05 (s, 1H), 7.90 (ddd, J = 9.2, 4.7,2.8 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 6.77 (s, 1H), 4.29 (ddt, J = 5.9,3.8, 1.9 Hz, 1H), 3.42-3.19 (m, 3H), 3.11 (dd, J = 18.7, 1.6 Hz, 1H),2.97-2.79 (m, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.51 (s, 3H), 2.16-2.03 (m,1H), 1.07 (dt, J = 8.6, 5.8 Hz, 1H), 0.23 (ddd, J = 7.3, 5.2, 2.1 Hz,1H). 31 505.1  1H NMR (400 MHz, acetone-d6) δ 9.03 (s, 1H), 8.65 (s,1H), 7.90 (ddd, J = 13.2, 7.4, 2.6 Hz, 1H), 7.84 (s, 1H), 7.51-7.41 (m,1H), 7.29 (dt, J = 10.6, 9.0 Hz, 1H), 4.25 (t, J = 7.3 Hz, 2H),3.50-3.30 (m, 4H), 3.01 (t, J = 7.5 Hz, 2H), 2.52 (s, 3H), 2.46 (p, J =7.5 Hz, 2H) 32 487.1  1H NMR (400 MHz, acetone-d6) δ 8.90 (s, 1H), 8.65(s, 1H), 7.84 (s, 1H), 7.80-7.72 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.24(t, J = 7.2 Hz, 2H), 3.46-3.34 (m, 4H), 3.00 (t, J = 7.5 Hz, 2H), 2.53(s, 3H), 2.46 (p, J = 7.4 Hz, 2H) 33 523.05 1H NMR (400 MHz, DMSO-d6) δ9.89 (s, 1H), 9.45 (s, 1H), 7.91 (dd, J = 6.9, 2.6 Hz, 1H), 7.75 (d, J =4.9 Hz, 1H), 7.56 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.38 (t, J = 9.1 Hz,1H), 4.28 (dd, J = 12.7, 6.0 Hz, 1H), 4.15 (d, J = 12.8 Hz, 1H), 2.95(td, J = 14.6, 7.8 Hz, 3H), 2.59 (d, J = 4.5 Hz, 5H), 2.40 (s, 3H), 2.33(d, J = 6.6 Hz, 1H), 1.21 (s, 2H), 0.43 (q, J = 4.3 Hz, 1H). 34 523.081H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.46 (s, 1H), 7.91 (dd, J =6.8, 2.6 Hz, 1H), 7.75 (d, J = 4.9 Hz, 1H), 7.56 (dt, J = 7.0, 4.3 Hz,1H), 7.38 (t, J = 9.1 Hz, 1H), 4.28 (dd, J = 12.7, 6.0 Hz, 2H), 4.15 (d,J = 12.8 Hz, 2H), 3.26 (s, 2H), 2.59 (d, J = 4.5 Hz, 5H), 2.40 (s, 3H),1.21 (d, J = 5.5 Hz, 3H), 0.43 (q, J = 4.4 Hz, 1H). 35 502.00 1H NMR(400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.42 (s, 1H), 8.14 (dd, J = 5.8, 2.7Hz, 1H), 7.94 (ddd, J = 9.2, 5.0, 2.8 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H),7.52 (t, J = 9.1 Hz, 1H), 4.14 (t, J = 7.2 Hz, 2H), 3.18 (s, 2H),2.99-2.85 (m, 4H), 2.59 (d, J = 4.6 Hz, 3H), 2.45 (s, 3H), 2.37 (t, J =7.4 Hz, 2H). 36 512.90 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.42(s, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.58 (dd, J = 10.4, 6.5 Hz, 2H), 4.13(t, J = 7.3 Hz, 2H), 3.20 (d, J = 12.9 Hz, 2H), 2.93 (t, J = 7.7 Hz,4H), 2.59 (d, J = 4.5 Hz, 3H), 2.43 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H).37 512.10 1H NMR (400 MHz, Acetone-d6) δ 9.17 (s, 1H), 8.67 (s, 1H),8.23 (dd, J = 5.7, 2.7 Hz, 1H), 8.04 (ddd, J = 9.1, 4.7, 2.8 Hz, 1H),7.84 (s, 1H), 7.42 (t, J = 9.0 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.52-3.28 (m, 4H), 3.01 (t, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.50-2.42 (m, 2H).38 525.09 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.42 (s, 1H), 7.80(q, J = 4.6 Hz, 1H), 7.66-7.52 (m, 2H), 4.24-4.17 (m, 1H), 3.23 (d, J =6.5 Hz, 1H), 3.19 (d, J = 6.6 Hz, 1H), 3.17-3.09 (m, 1H), 3.05 (s, 1H),3.01 (s, 1H), 2.91-2.78 (m, 1H), 2.60 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H),2.15-2.05 (m, 1H), 1.05 (dt, J = 8.5, 5.7 Hz, 1H), 0.12 (td, J = 5.3,2.0 Hz, 1H). 39 533.02 1H NMR (400 MHz, Acetonitrile-d3) δ 12.77 (s,1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.89 (dd, J = 6.8, 2.6 Hz, 1H), 7.72(s, 1H), 7.53 (ddd, J = 8.9, 4.1, 2.6 Hz, 1H), 7.23 (t, J = 9.1 Hz, 1H),4.28 (s, 1H), 3.32 (m, 4H), 3.23 (dd, J = 18.7, 6.8 Hz, 1H), 3.00 (d, J= 18.7 Hz, 1H), 2.48 (s, 3H), 1.06 (dt, J = 8.5, 5.8 Hz, 1H), 0.28-0.20(m, 1H) 40 535.07 1H NMR (400 MHz, Acetonitrile-d3) δ 12.86 (s, 1H),8.33 (s, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.48 (dd, J = 10.2, 6.4 Hz,2H), 4.26 (td, J = 6.0, 3.0 Hz, 1H), 3.32 (m, 4H), 3.23 (dd, J = 18.7,6.8 Hz, 1H), 3.06-2.95 (d, J = 18.7 Hz,1H), 2.47 (s, 3H), 2.06 (p, J =6.1 Hz, 1H), 1.06 (dt, J = 8.6, 5.8 Hz, 1H), 0.24 (td, J = 5.4, 2.1 Hz,1H) 41 524.13 1H NMR (400 MHz, Acetonitrile-d3) δ 8.41- 8.31 (m, 1H),8.07 (dd, J = 5.7, 2.7 Hz, 1H), 8.05 (s, 1H), 7.88 (ddd, J = 9.2, 4.8,2.8 Hz, 1H), 7.73 (s, 1H), 7.32 (t, J = 9.0 Hz, 1H), 4.28 (tt, J = 5.9,1.9 Hz, 1H), 3.43-3.27 (m, 4H), 3.23 (dd, J = 18.7, 6.8 Hz, 1H), 3.00(d, J = 18.7 Hz, 1H), 2.49 (s, 3H), 2.11-2.01 (m, 1H), 1.06 (dt, J =8.6, 5.8 Hz, 1H), 0.29-0.18 (m, 1H): 42 517.11 1H NMR (400 MHz,Acetonitrile-d3) δ 8.27 (s, 1H), 8.03 (s, 1H), 7.77 (ddd, J = 12.9, 7.4,2.5 Hz, 1H), 7.73 (s, 1H), 7.38-7.29 (m, 1H), 7.25 (dt, J = 10.5, 8.9Hz, 1H), 4.27 (td, J = 6.1, 3.1 Hz, 1H), 3.42-3.27 (m, 4H), 3.23 (dd, J= 18.6, 6.8 Hz, 1H), 3.00 (dd, J = 18.8, 1.6 Hz, 1H), 2.48 (s, 3H),2.14-2.00 (m, 1H), 1.06 (dt, J = 8.6, 5.8 Hz, 1H), 0.28-0.20 (m, 1H) 43455.20 1H NMR (400 MHz, Acetone-d6) δ 9.02 (s, 1H), 8.45 (s, 1H),7.95-7.86 (m, 1H), 7.65 (s, 1H), 7.48-7.42 (m, 1H), 7.35-7.25 (m, 1H),4.25 (t, J = 7.3 Hz, 2H), 3.07 (t, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.46(p, J = 7.5 Hz, 2H), 1.44-1.29 (m, 4H). 44 495.10 1H NMR (400 MHz,DMSO-d6) δ 10.00 (s, 1H), 9.42 (s, 1H), 7.86-7.71 (m, 2H), 7.39 (qd, J =4.8, 2.5 Hz, 2H), 4.13 (t, J = 7.3 Hz, 2H), 3.28- 3.12 (m, 2H), 2.93 (t,J = 7.5 Hz, 3H), 2.59 (d, J = 4.5 Hz, 3H), 2.43 (s, 3H), 2.37 (t, J =7.3 Hz, 2H). 45 489.20 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.45(s, 1H), 7.96 (dd, J = 6.8, 2.6 Hz, 1H), 7.60 (m, 2H), 7.41 (t, J = 9.1Hz, 1H), 5.84-5.60 (m, 1H), 4.46 (m, 1H), 4.38 (m, 1H), 3.34 (ddd, J =37.1, 18.8, 5.0 Hz, 1H), 3.12 (dd, J = 26.7, 18.9 Hz, 1H), 2.46 (s, 3H),1.34-1.19 (m, 4H). 46 489.20 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H),9.45 (s, 1H), 7.96 (dd, J = 6.9, 2.6 Hz, 1H), 7.60 (m, 2H), 7.41 (t, J =9.1 Hz, 1H), 5.72 (m, 1H), 4.48-4.36 (m, 2H), 3.34 (ddd, J = 37.1, 18.8,5.0 Hz, 1H), 3.12 (dd, J = 26.7, 18.8 Hz, 1H), 2.46 (s, 3H), 1.38-1.18(m, 4H). 47 477.20 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.41 (s,1H), 7.77 (d, J = 4.9 Hz, 1H), 7.71-7.58 (m, 2H), 7.16 (t, J = 8.9 Hz,2H), 4.13 (t, J = 7.2 Hz, 2H), 3.18 (t, J = 13.8 Hz, 2H), 2.92 (t, J =7.5 Hz, 4H), 2.59 (d, J = 4.6 Hz, 3H), 2.44 (s, 3H), 2.37 (t, J = 7.3Hz, 2H). 48 505.20 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.73 (s,1H), 7.82 (s, 1H), 7.72-7.62 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H),5.83-5.56 (m, 1H), 4.53- 4.32 (m, 2H), 3.38-3.14 (m, 5H), 2.98 (dd, J =26.7, 18.8 Hz, 1H), 2.46 (s, 3H). 49 513.10 1H NMR (400 MHz, DMSO-d6) δ10.06 (s, 1H), 9.48 (s, 1H), 7.93 (q, J = 4.5 Hz, 1H), 7.88-7.78 (m,1H), 7.49-7.36 (m, 2H), 5.86-5.60 (m, 1H), 4.53-4.41 (m, 1H), 4.41-4.34(m, 1H), 3.40 (td, J = 18.8, 5.0 Hz, 1H), 3.33-3.25 (m, 1H), 3.23 (m,1H), 3.14 (m, 1H), 3.11-2.94 (m, 1H), 2.95-2.78 (m, 1H), 2.61 (d, J =4.5 Hz, 3H), 2.48 (s, 3H). 50 486.0  1H NMR (400 MHz, Acetone-d6) δ 9.02(s, 1H), 8.54 (s, 1H), 8.09-7.95 (m, 1H), 7.66 (ddd, J = 9.0, 4.2, 2.6Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H), 4.31 (s, 3H), 4.26 (d, J = 6.7 Hz,2H), 3.13 (t, J = 7.6 Hz, 2H), 2.56 (s, 3H), 2.54-2.41 (m, 2H),1.57-1.50 (m, 2H), 1.49-1.41 (m, 2H). 51 473.1  1H NMR (400 MHz,Methanol-d4) δ 7.87 (dd, J = 6.7, 2.6 Hz, 1H), 7.51 (ddd, J = 8.9, 4.1,2.6 Hz, 1H), 7.21 (t, J = 9.0 Hz, 1H), 4.20 (t, J = 7.3 Hz, 2H), 3.08(t, J = 7.3 Hz, 2H), 2.53 (s, 3H), 2.52-2.41 (m, 5H), 1.63-1.39 (m, 4H).52 483.1  1H NMR (400 MHz, Chloroform-d) δ 7.81 (dd, J = 6.5, 2.6 Hz,1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.38 (ddd, J = 8.9, 4.0,2.8 Hz, 1H), 7.12 (t, J = 8.7 Hz, 1H), 5.56 (s, 2H), 4.53-4.41 (m, 1H),3.67-3.57 (m, 2H), 3.51 (dd, J = 19.0, 6.9 Hz, 1H), 3.31-3.16 (m, 1H),2.61 (s, 3H), 2.06 (p, J = 6.0 Hz, 1H), 1.54-1.45 (m, 2H), 1.38-1.30 (m,2H), 1.25 (s, 1H), 1.10 (dt, J = 8.6, 6.0 Hz, 1H), 0.96-0.86 (m, 2H),0.35- 0.26 (m, 1H), −0.03 (s, 9H).; 1H NMR (400 MHz, Acetonitrile-d3) δ12.58 (s, 1H), 8.26 (s, 1H), 7.94 (s, 1H), 7.89 (dd, J = 6.8, 2.6 Hz,1H), 7.53 (m, 2H), 7.23 (t, J = 9.1 Hz, 1H), 4.29 (dd, J = 7.0, 5.0 Hz,1H), 3.30 (dd, J = 18.7, 6.8 Hz, 1H), 3.08 (d, J = 18.9 Hz, 1H), 2.49(s, 3H), 2.07 (p, J = 6.9, 6.3 Hz, 1H), 1.48-1.17 (m, 5H), 1.06 (dt, J =8.5, 5.8 Hz, 1H), 0.25 (td, J = 5.5, 2.0 Hz, 1H). 53 523.1  1H NMR (400MHz, Acetone-d6) δ 9.13 (s, 1H), 8.66 (s, 1H), 7.83 (s, 1H), 7.63 (dd, J= 10.2, 6.5 Hz, 2H), 4.30-4.22 (m, 2H), 3.49-3.34 (m, 4H), 3.01 (t, J =7.5 Hz, 2H), 2.52 (s, 3H), 2.47 (q, J = 7.4 Hz, 2H). 54 499.1  1H NMR(400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.84 (s, 1H), 9.40 (s, 1H), 7.96(dd, J = 6.8, 2.7 Hz, 1H), 7.60 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.39(t, J = 9.1 Hz, 1H), 4.23 (t, J = 6.0 Hz, 1H), 3.20 (dd, J = 18.5, 6.8Hz, 1H), 3.05-2.95 (m, 1H), 2.39 (s, 3H), 2.18-2.06 (m, 1H), 1.64 (t, J= 3.9 Hz, 2H), 1.44 (d, J = 2.9 Hz, 2H), 1.07 (dt, J = 8.6, 5.7 Hz, 1H).55 520.1  1H NMR (400 MHz, Methanol-d4) δ 8.49 (d, J = 5.7 Hz, 1H), 8.02(s, 1H), 7.85 (s, 1H), 7.79 (d, J = 5.6 Hz, 1H), 6.69 (t, J = 55.2 Hz,1H), 4.21 (t, J = 7.2 Hz, 2H), 3.34 (s, 0H), 3.30 (s, 0H), 2.88- 2.79(m, 2H), 2.65-2.38 (m, 4H), 2.26 (t, J = 7.4 Hz, 2H), 1.63-1.54 (m, 2H).56 482.2  1H NMR (400 MHz, Acetonitrile-d3) δ 8.61 (s, 1H), 8.54 (d, J =5.6 Hz, 1H), 7.98 (d, J = 2.3 Hz, 2H), 7.79-7.69 (m, 1H), 7.55 (s, 1H),6.70 (t, J = 55.4 Hz, 1H), 4.30 (t, J = 6.1 Hz, 1H), 3.31 (dd, J = 18.7,6.8 Hz, 1H), 3.09 (d, J = 18.7 Hz, 1H), 2.51 (s, 3H), 2.08 (p, J = 6.1Hz, 1H), 1.35 (d, J = 3.9 Hz, 2H), 1.29 (dd, J = 11.9, 4.9 Hz, 3H), 1.07(dt, J = 8.5, 5.8 Hz, 1H), 0.33-0.18 (m, 1H). 57 502   1H NMR (400 MHz,DMSO-d6) δ 10.25 (s, 1H), 9.84 (s, 1H), 9.39 (s, 1H), 7.60 (dd, J =10.4, 6.4 Hz, 2H), 4.22 (t, J = 6.0 Hz, 1H), 3.21 (dd, J = 18.6, 6.8 Hz,1H), 3.00 (d, J = 18.6 Hz, 1H), 2.38 (s, 3H), 2.19-2.07 (m, 1H), 1.64(d, J = 2.9 Hz, 2H), 1.44 (d, J = 2.9 Hz, 2H), 1.07 (dt, J = 8.5, 5.8Hz, 1H), 0.22-0.13 (m, 1H). 58 491.1  1H NMR (400 MHz, DMSO-d6) δ 10.25(s, 1H), 9.84 (s, 1H), 9.40 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H),7.96 (ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 4.24 (t,J = 6.1 Hz, 1H), 3.21 (dd, J = 18.5, 6.7 Hz, 1H), 3.00 (d, J = 18.6 Hz,1H), 2.40 (s, 3H), 2.13 (q, J = 7.2, 6.7 Hz, 1H), 1.64 (d, J = 2.8 Hz,2H), 1.45 (t, J = 4.0 Hz, 2H), 1.07 (dt, J = 8.6, 5.8 Hz, 1H), 0.23-0.12(m, 1H). 59 538.1  1H NMR (400 MHz, Acetone-d6) δ 8.93 (s, 1H), 8.71 (s,1H), 8.53 (t, J = 5.7 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 7.85 (s, 1H),6.94 (t, J = 53.5 Hz, 1H), 4.33 (t, J = 7.3 Hz, 2H), 3.54-3.27 (m, 4H),3.02 (q, J = 7.0 Hz, 2H), 2.65 (s, 3H), 2.49 (p, J = 7.5 Hz, 2H). 60478.1  1H NMR (400 MHz, Acetone-d6) δ 9.00 (s, 1H), 8.50 (s, 1H), 8.05(dd, J = 6.8, 2.6 Hz, 1H), 7.66 (ddd, J = 8.9, 4.2, 2.6 Hz, 1H), 7.29(t, J = 9.0 Hz, 1H), 4.31-4.22 (m, 2H), 3.34-3.10 (m, 6H), 3.04 (s, 1H),2.54 (s, 3H), 2.49 (p, J = 7.5 Hz, 2H). 61 484   1H NMR (400 MHz,DMSO-d6) δ 10.14 (s, 1H), 9.84 (s, 1H), 9.40 (s, 1H), 7.88-7.76 (m, 1H),7.44-7.37 (m, 2H), 4.23 (t, J = 5.8 Hz, 1H), 3.20 (dd, J = 18.6, 6.7 Hz,1H), 3.00 (d, J = 18.6 Hz, 1H), 2.39 (s, 3H), 2.11 (d, J = 7.5 Hz, 1H),1.64 (d, J = 2.9 Hz, 2H), 1.45 (t, J = 4.0 Hz, 2H), 1.12-1.01 (m, 1H),0.17 (d, J = 6.9 Hz, 1H). 62 499.2  1H NMR (400 MHz, Chloroform-d) δ8.97 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.77-7.67 (m, 2H), 6.62 (t, J = 55.4 Hz, 1H), 4.50 (td, J =5.8, 2.8 Hz, 1H), 3.54 (dd, J = 19.1, 6.9 Hz, 1H), 3.38-3.19 (m, 1H),2.65 (s, 3H), 2.16-2.06 (m, 1H), 1.95- 1.86 (m, 2H), 1.57-1.51 (m, 2H),1.14 (dt, J = 8.7, 6.0 Hz, 1H), 0.34 (td, J = 6.6, 5.8, 2.0 Hz, 1H). 63500.2  1H NMR (400 MHz, Acetonitrile-d3) δ 8.51 (t, J = 5.7 Hz, 1H),8.40 (d, J = 5.3 Hz, 2H), 7.96 (s, 1H), 7.53 (s, 1H), 6.90 (t, J = 53.5Hz, 1H), 4.36 (ddt, J = 5.8, 3.7, 1.9 Hz, 1H), 3.32 (dd, J = 18.8, 6.8Hz, 1H), 3.11 (d, J = 18.8 Hz, 1H), 2.58 (s, 3H), 2.12-2.05 (m, 1H),1.42-1.19 (m, 4H), 1.11 (dt, J = 8.6, 5.8 Hz, 1H), 0.32 (td, J = 5.6,2.1 Hz, 1H). 64 486.0  1H NMR (400 MHz, Methanol-d4) δ 7.87 (dd, J =6.8, 2.5 Hz, 1H), 7.57-7.44 (m, 1H), 7.21 (t, J = 9.0 Hz, 1H), 4.21 (t,J = 7.2 Hz, 2H), 3.11 (t, J = 7.5 Hz, 2H), 2.51 (m, 8H), 1.64 (t, J =4.0 Hz, 2H), 1.48 (t, J = 4.0 Hz, 2H). 65 488.0  1H NMR (400 MHz,Methanol-d4) δ 7.65-7.32 (m, 2H), 4.21 (t, J = 7.3 Hz, 2H), 3.11 (t, J =7.4 Hz, 2H), 2.51 (d, J = 13.1 Hz, 8H), 1.73-1.58 (m, 2H), 1.55-1.38 (m,2H). 66 480.0  1H NMR (400 MHz, Methanol-d4) δ 7.86 (dd, J = 6.7, 2.6Hz, 1H), 7.50 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.37 (dd, J = 8.3, 1.4Hz, 2H), 7.30 (dd, J = 8.5, 6.8 Hz, 2H), 7.25-7.14 (m, 2H), 4.16 (t, J =7.2 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.51 (s, 3H), 2.45-2.31 (m, 2H),1.29 (s, 3H). 67 481.9  1H NMR (400 MHz, Methanol-d4) δ 7.46 (dd, J =10.0, 6.4 Hz, 2H), 7.41-7.25 (m, 4H), 7.21 (d, J = 7.1 Hz, 1H), 4.16 (t,J = 7.2 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.50 (s, 3H), 2.45-2.32 (m,1H), 1.29 (s, 4H). 68 517.2  (NOTE: suspected mixture of rotamers) 1HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 0H), 10.18 (s, 1H), 9.86 (s, 1H),9.39 (d, J = 8.2 Hz, 1H), 8.45 (dd, J = 17.8, 5.3 Hz, 1H), 8.24 (t, J =5.7 Hz, 1H), 7.14 (td, J = 53.1, 4.2 Hz, 1H), 4.26 (d, J = 34.2 Hz, 1H),3.19 (td, J = 20.5, 19.7, 6.7 Hz, 1H), 3.01 (d, J = 18.3 Hz, 1H), 2.44(d, J = 20.7 Hz, 3H), 2.21-2.07 (m, 1H), 1.65 (t, J = 4.4 Hz, 2H), 1.47(dd, J = 16.1, 5.3 Hz, 2H), 1.16-1.03 (m, 1H), 0.22 (d, J = 19.8 Hz,1H). 69 436.9  1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.36 (s, 1H),7.65-7.52 (m, 2H), 7.44-7.30 (m, 2H), 6.89 (td, J = 8.5, 8.1, 2.2 Hz,1H), 4.12 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.41 (s, 3H),2.40-2.34 (m, 2H), 1.31-1.23 (m, 2H), 1.20 (t, J = 3.2 Hz, 2H). 70437.0  1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.35 (s, 1H), 7.72-7.59(m, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 8.9 Hz, 2H), 4.11 (t, J= 7.3 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.42 (d, J = 2.2 Hz, 3H), 2.36(q, J = 7.4 Hz, 1H), 1.26 (d, J = 8.5 Hz, 2H), 1.23-1.15 (m, 1H). 71494.2  1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.96 (dd, J = 6.8, 2.6Hz, 1H), 7.60 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H),4.52- 4.42 (m, 2H), 4.32 (d, J = 3.5 Hz, 1H), 4.29 (d, J = 3.4 Hz, 1H),4.28-4.19 (m, 1H), 3.27-3.21 (m, 1H), 3.04 (d, J = 18.5 Hz, 1H), 2.39(s, 3H), 2.15 (q, J = 6.6 Hz, 1H), 1.67 (s, 3H), 1.11-1.03 (m, 1H), 0.17(t, J = 5.0 Hz, 1H). 72 485   1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H),8.17 (dd, J = 5.8, 2.7 Hz, 2H), 7.96 (ddd, J = 9.3, 4.9, 2.7 Hz, 2H),7.52 (t, J = 9.1 Hz, 2H), 4.52- 4.42 (m, 4H), 4.35-4.21 (m, 6H), 3.55(s, 7H), 3.30-3.20 (m, 2H), 3.05 (d, J = 18.4 Hz, 2H), 2.40 (s, 6H),2.19-2.10 (m, 2H), 1.67 (s, 6H), 1.08 (dt, J = 8.7, 5.9 Hz, 2H), 0.18(dd, J = 10.8, 2.0 Hz, 1H), 0.17 (s, 1H). 73 496.1  1H NMR (400 MHz,DMSO-d6) δ 9.39 (s, 2H), 7.60 (dd, J = 10.3, 6.4 Hz, 4H), 4.52-4.42 (m,4H), 4.35-4.19 (m, 7H), 3.55 (s, 7H), 3.29- 3.20 (m, 2H), 3.05 (d, J =18.6 Hz, 2H), 2.39 (s, 7H), 2.15 (s, 2H), 2.20-2.09 (m, 1H), 1.66 (s,6H), 1.08 (dt, J = 8.5, 5.8 Hz, 2H), 0.17 (t, J = 5.7 Hz, 2H). 74 452.991H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.36 (s, 1H), 7.82 (t, J = 2.0Hz, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.34 (t, J = 8.1 Hz, 1H), 7.12 (dt, J= 8.1, 1.5 Hz, 1H), 4.12 (t, J = 7.3 Hz, 2H), 2.91- 2.80 (m, 2H), 2.42(s, 3H), 2.40-2.34 (m, 2H), 1.31-1.22(m, 2H), 1.22-1.14 (m, 2H). 75444.0  1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.37 (s, 1H), 8.10 (q,J = 1.3 Hz, 1H), 7.90 (dt, J = 6.6, 2.5 Hz, 1H), 7.61-7.49 (m, 3H), 4.13(t, J = 7.2 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.38 (t, J= 7.4 Hz, 2H), 1.25 (t, J = 3.2 Hz, 2H), 1.20 (t, J = 3.5 Hz, 2H). 76454.99 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.37 (s, 1H), 7.56 (s,1H), 7.38 (dd, J = 9.6, 2.3 Hz, 2H), 6.97-6.86 (m, 1H), 4.12 (t, J = 7.3Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.44-2.32 (m, 5H), 1.25 (t, J = 3.1Hz, 2H), 1.22-1.12 (m, 2H). 77 454.99 1H NMR (400 MHz, DMSO-d6) δ 10.13(s, 1H), 9.37 (s, 1H), 7.56 (s, 1H), 7.38 (dd, J = 9.6, 2.3 Hz, 2H),6.97-6.86 (m, 1H), 4.12 (t, J = 7.3 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H),2.44-2.32 (m, 5H), 1.25 (t, J = 3.1 Hz, 2H), 1.22-1.12 (m, 2H). 78532.23 1H NMR (400 MHz, Acetonitrile-d3) δ 8.79 (s, 1H), 8.57 (d, J =5.9 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.88 (dd, J = 6.0,2.1 Hz, 1H), 7.73 (s, 1H), 6.82 (t, J = 54.7 Hz, 1H), 4.35- 4.25 (m,1H), 3.40-3.19 (m, 5H), 3.07-2.96 (m, 1H), 2.51 (s, 3H), 2.08 (dt, J =13.1, 6.2 Hz, 1H), 1.08 (dt, J = 8.6, 5.9 Hz, 1H), 0.31-0.22 (m, 1H). 79474.14 1H NMR (400 MHz, Acetonitrile-d3) δ 8.36 (s, 1H), 8.11-8.04 (m,1H), 7.93 (s, 1H), 7.92- 7.84 (m, 1H), 7.55 (s, 1H), 7.32 (t, J = 9.0Hz, 1H), 4.29 (m, 1H), 3.31 (dd, J = 18.4, 6.8 Hz, 1H), 3.09 (d, J =18.5 Hz, 1H), 2.50 (s, 3H), 2.10 (m, 1H), 1.33 (d, J = 19.4 Hz, 4H),1.06 (q, J = 6.5 Hz, 1H), 0.25 (s, 1H). 80 550.17 1H NMR (400 MHz,Acetonitrile-d3) δ 8.52 (t, J = 5.7 Hz, 1H), 8.43 (s, 1H), 8.41 (d, J =5.5 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 6.92 (t, J = 53.4 Hz, 1H), 4.35(tt, J = 6.0, 1.9 Hz, 1H), 3.43- 3.28 (m, 3H), 3.24 (dd, J = 18.7, 6.8Hz, 1H), 3.07-2.97 (m, 1H), 2.57 (s, 3H), 2.15-2.04 (m, 1H), 1.10 (dt, J= 8.6, 5.8 Hz, 1H), 0.31 (td, J = 5.5, 2.1 Hz, 1H). 81 467.11 1H NMR(400 MHz, Acetonitrile-d3) δ 8.27 (s, 1H), 7.92 (s, 1H), 7.77 (ddd, J =13.1, 7.4, 2.5 Hz, 1H), 7.55 (s, 1H), 7.37-7.29 (m, 1H), 7.25 (dt, J =10.5, 8.9 Hz, 1H), 3.31 (dd, J = 18.7, 6.8 Hz, 1H), 3.08 (d, J = 18.6Hz, 1H), 2.49 (s, 3H), 2.08 (q, J = 7.7 Hz, 1H), 1.39-1.33 (m, 2H),1.33-1.23 (m, 2H), 1.06 (dt, J = 8.6, 5.8 Hz, 1H), 0.25 (td, J = 5.5,2.1 Hz, 1H). 82 463.1  1H NMR (400 MHz, Methanol-d4) δ 7.87 (dd, J =6.7, 2.6 Hz, 1H), 7.50 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 7.21 (t, J = 9.0Hz, 1H), 4.20 (t, J = 7.3 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.74 (s,3H), 2.51 (m, 5H), 1.54 (s, 6H). 83 465.0  1H NMR (400 MHz, Methanol-d4)δ 7.47 (dd, J = 10.0, 6.3 Hz, 2H), 4.20 (t, J = 7.3 Hz, 2H), 3.06 (t, J= 7.5 Hz, 2H), 2.74 (s, 3H), 2.50 (m, 5H), 1.54 (s, 6H). 84 489.0  1HNMR (400 MHz, Methanol-d4) δ 7.83-7.71 (m, 1H), 7.69 (s, 1H), 7.14 (td,J = 9.1, 2.1 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.7 Hz,2H), 2.58 (s, 3H), 2.54-2.37 (m, 2H), 1.51- 1.24 (m, 4H). 85 503.0  1HNMR (400 MHz, Methanol-d4) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.58-7.48 (m,1H), 7.41 (t, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.20 (t, J =7.2 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 2.48 (q, J = 7.2Hz, 2H), 1.45-1.28 (m, 4H). 86 471.0  1H NMR (400 MHz, Methanol-d4) δ8.20-7.99 (m, 1H), 7.69 (s, 1H), 7.28-7.10 (m, 2H), 4.25 (t, J = 7.2 Hz,2H), 2.96 (t, J = 7.6 Hz, 2H), 2.48 (q, J = 7.4 Hz, 2H), 1.49-1.27 (m,4H). 87 483.12 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.13 (s, 1H),9.79 (s, 1H), 7.88-7.75 (m, 2H), 7.45-7.34 (m, 2H), 4.89 (dt, J = 13.0,6.8 Hz, 4H), 4.21 (t, J = 5.5 Hz, 1H), 3.11 (dd, J = 18.5, 6.7 Hz, 1H),2.90 (d, J = 18.5 Hz, 1H), 2.38 (s, 3H), 2.13-2.03 (m, 1H), 1.05 (dt, J= 8.1, 5.5 Hz, 1H), 0.19-0.12 (m, 1H). 88 487.12 1H NMR (400 MHz,DMSO-d6) δ 11.05 (a, 1H), 9.98 (s, 1H), 9.80 (s, 1H), 7.93 (dd, J = 6.9,2.4 Hz, 1H), 7.78 (s, 1H), 7.61-7.54 (m, 1H), 7.38 (t, J = 9.2 Hz, 1H),4.94-4.84 (m, 4H), 4.12 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H),2.65 (dt, J = 3.6, 1.6 Hz, 1H), 2.42 (s, 3H), 2.41-2.33 (m, 2H), 2.31(dt, J = 3.3, 1.5 Hz, 1H). 89 537.1  1H NMR (400 MHz, Acetone-d6) δ 9.07(s, 1H), 8.68 (s, 1H), 8.08 (dd, J = 6.3, 2.6 Hz, 1H), 7.95- 7.87 (m,1H), 7.84 (s, 1H), 7.27 (t, J = 9.5 Hz, 1H), 7.10 (t, J = 54.7 Hz, 1H),4.25 (t, J = 7.3 Hz, 2H), 3.49-3.28 (m, 4H), 3.00 (t, J = 7.5 Hz, 2H),2.54 (s, 3H), 2.46 (q, J = 7.4 Hz, 2H). 90 473.1  1H NMR (400 MHz,Acetone-d6) δ 8.47 (s, 1H), 8.29-8.21 (m, 1H), 7.65 (s, 1H), 7.45-7.34(m, 1H), 4.31 (t, J = 7.3 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.63 (s,3H), 2.48 (t, J = 7.4 Hz, 2H), 1.37 (d, J = 13.0 Hz, 4H). 91 489.2  1HNMR (400 MHz, Acetone-d6) δ 8.47 (s, 1H), 8.42-8.34 (m, 1H), 7.65 (s,1H), 7.39 (dd, J = 10.6, 9.1 Hz, 1H), 4.30 (t, J = 7.3 Hz, 2H), 3.08 (t,J = 7.5 Hz, 2H), 2.63 (s, 3H), 2.49 (q, J = 7.4 Hz, 2H), 1.42-1.30 (m,4H). 92 430.1  1H NMR (400 MHz, Methanol-d4) 7.48 (dd, J = 10.0, 6.4 Hz,1H), 4.21 (t, J = 7.5 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 2.58 (s, 1H),2.50 (s, 3H), 2.50 (d, J = 7.5 Hz, 2H), 1.32-1.22 (m, 2H), 1.17-1.11 (m,2H). 93 455.1  1H NMR (400 MHz, Methanol-d4) δ 7.80 (td, J = 8.8, 5.9Hz, 1H), 7.69 (s, 1H), 7.07 (ddd, J = 10.9, 8.8, 2.8 Hz, 1H), 7.01-6.92(m, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.02-2.90 (m, 2H), 2.58 (s, 3H),2.51-2.41 (m, 2H), 1.48-1.29 (m, 4H). 94 428.1  1H NMR (400 MHz,Methanol-d4) δ 9.72 (s, 1H), 9.25 (s, 1H), 7.88 (dt, J = 6.7, 2.4 Hz,1H), 7.51 (ddt, J = 8.9, 4.3, 2.2 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H),4.22 (t, J = 7.5 Hz, 3H), 3.10 (t, J = 7.5 Hz, 2H), 2.59 (s, 1H), 2.53(s, 3H), 4.53 (t, J = 7.5 Hz, 3H), 1.32-1.09 (m, 4H). 95 489.2  1H NMR(400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.41 (s, 1H), 7.79 (q, J = 4.6 Hz,1H), 7.74-7.64 (m, 2H), 7.22-7.11 (m, 2H), 4.22 (s, 1H), 3.30- 3.00 (m,4H), 3.02-2.90 (m, 1H), 2.60 (d, J = 4.6 Hz, 3H), 2.40 (s, 3H),2.15-2.03 (m, 2H), 1.05 (dt, J = 8.5, 5.7 Hz, 1H), 0.14 (td, J = 5.4,2.1 Hz, 1H). 96 507   1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.41(s, 1H), 7.88-7.76 (m, 2H), 7.45-7.33 (m, 2H), 4.22 (s, 1H), 3.25 (dd, J= 11.1, 3.8 Hz, 1H), 3.25-3.10 (m, 2H), 3.05 (s, 1H), 2.98 (d, J = 16.1Hz, 1H), 2.95-2.79 (m, 1H), 2.60 (d, J = 4.6 Hz, 3H), 2.40 (s, 3H),2.16-2.04 (m, 1H), 1.05 (dt, J = 8.4, 5.7 Hz, 1H), 0.13 (td, J = 5.3,2.1 Hz, 1H). 98 485.1  1H NMR (400 MHz, Methanol-d4) δ 7.87 (dd, J =6.7, 2.7 Hz, 1H), 7.82 (s, 1H), 7.51 (ddd, J = 9.0, 4.1, 2.5 Hz, 1H),7.22 (t, J = 8.9 Hz, 1H), 4.20 (t, J = 7.3 Hz, 2H), 4.07 (s, 3H),3.03-2.92 (t, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.47 (quin, J = 7.4 Hz,2H), 1.48-1.27 (m, 4H). 99 449.2  1H NMR (400 MHz, DMSO-d6) δ 9.95 (s,1H), 9.34 (s, 1H), 7.73-7.65 (m, 2H), 7.22-7.10 (m, 2H), 4.21 (s, 1H),3.14 (dd, J = 18.5, 6.7 Hz, 2H), 2.93 (d, J = 17.5 Hz, 2H), 2.38 (s,3H), 2.09 (p, J = 6.1 Hz, 1H), 1.30-1.16 (m, 5H), 1.06 (dt, J = 8.6, 5.8Hz, 1H), 0.16 (td, J = 5.3, 2.0 Hz, 1H). 100 500.00 1H NMR (400 MHz,DMSO-d6) δ 9.96 (s, 2H), 9.60 (s, 1H), 7.76-7.64 (m, 4H), 7.16 (t, J =8.8 Hz, 4H), 4.21 (s, 2H), 3.25 (d, J = 13.6 Hz, 6H), 3.04 (dd, J =18.5, 6.7 Hz, 2H), 2.89-2.78 (m, 2H), 2.37 (s, 6H), 2.08 (s, 3H), 1.21(s, 1H), 1.15- 1.00 (m, 2H), 0.15 (s, 2H). 101 471.1  1H NMR (400 MHz,DMSO-d6) δ 10.10 (s, 1H), 9.38 (s, 1H), 7.61-7.58 (m, 1H), 7.57-7.51 (m,2H), 7.11 (dt, J = 8.6, 2.2 Hz, 1H), 4.12 (t, J = 7.2 Hz, 2H), 2.86 (t,J = 7.5 Hz, 2H), 2.41 (s, 3H), 2.40-2.33 (m, 2H), 1.30-1.22 (m, 2H),1.22-1.16 (m, 2H). 102 487.0  1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H),9.38 (s, 1H), 7.74 (d, J = 1.9 Hz, 2H), 7.56 (s, 1H), 7.29 (t, J = 1.9Hz, 1H), 4.12 (t, J = 7.3 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.42 (s,3H), 2.37 (q, J = 7.6 Hz, 2H), 1.32-1.22 (m, 2H), 1.22- 1.13 (m, 2H).103 469.1  1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.37 (s, 1H), 7.95(s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.46 (t, J = 7.9 Hz,1H), 7.25 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 55.9 Hz, 1H), 4.13 (t, J =7.2 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.38 (t, J = 7.3Hz, 2H), 1.32-1.23 (m, 2H), 1.23-1.14 (m, 2H). 104 452.1  1H NMR (400MHz, Acetone-d6) δ 9.03 (s, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.67 (dd, J =8.7, 3.7 Hz, 1H), 7.46 (s, 1H), 7.29 (t, J = 9.0 Hz, 1H), 4.32-4.22 (m,2H), 3.82-3.65 (m, 4H), 3.16 (t, J = 7.6 Hz, 2H), 2.53 (s, 3H), 2.49 (q,J = 7.5 Hz, 2H), 1.36 (s, 3H). 105 461.02 1H NMR (400 MHz, DMSO-d6) δ9.91 (s, 1H), 8.95 (s, 1H), 7.90 (dd, J = 6.8, 2.6 Hz, 1H), 7.58 (q, J =4.5 Hz, 1H), 7.53 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.34 (t, J = 9.1 Hz,1H), 4.08 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.53 (d, J =4.6 Hz, 3H), 2.37 (s, 3H), 2.32 (p, J = 7.6 Hz, 2H), 1.23 (q, J = 4.4Hz, 2H), 0.88 (q, J = 4.4 Hz, 2H). 106 473.1  1H NMR (400 MHz,Acetone-d6) δ 9.01 (s, 1H), 8.25 (s, 1H), 8.09-8.02 (m, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H), 6.76 (s, 1H), 6.26 (s, 1H),4.26 (t, J = 7.3 Hz, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H),2.52-2.44 (m, 2H), 2.34 (s, 6H). 107 471.1  1H NMR (400 MHz, DMSO-d6) δ9.67 (s, 1H), 9.39 (s, 1H), 7.67 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.56(s, 1H), 7.39 (ddd, J = 8.3, 6.7, 1.6 Hz, 1H), 7.21 (td, J = 8.1, 1.4Hz, 1H), 4.14 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.49 (s,3H), 2.37 (p, J = 7.6 Hz, 2H), 1.30-1.23 (m, 2H), 1.20 (dd, J = 5.9, 2.3Hz, 2H). 111 473.2  1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.39 (s,1H), 7.56 (s, 1H), 7.51-7.39 (m, 1H), 7.39-7.26 (m, 1H), 4.13 (t, J =7.2 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.46 (s, 3H), 2.38 (q, J = 7.3Hz, 2H), 1.28-1.23 (m, 2H), 1.22-1.15 (m, 2H). 112 455.1  1H NMR (400MHz, Acetone-d6) δ 9.04 (s, 1H), 8.51 (s, 1H), 8.04 (ddd, J = 6.8, 2.7,1.7 Hz, 1H), 7.65 (dtd, J = 8.8, 2.6, 1.3 Hz, 1H), 7.28 (t, J = 9.0 Hz,1H), 4.25 (t, J = 7.3 Hz, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.65 (s, 7H),2.57-2.41 (m, 2H), 2.51 (s, 3H). 113 439.1  1H NMR (400 MHz, Acetone-d6)δ 9.06 (s, 1H), 8.49 (s, 1H), 7.91 (ddd, J = 13.1, 7.4, 2.5 Hz, 1H),7.45 (ddt, J = 8.4, 4.0, 1.7 Hz, 1H), 7.30 (dt, J = 10.5, 9.0 Hz, 1H),4.25 (t, J = 7.3 Hz, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.65 (s, 6H),2.53-2.43 (m, 2H), 2.51 (s, 3H). 114 1H NMR (400 MHz, Methanol-d4) δ7.99-7.86 (m, 1H), 7.76 (dd, J = 8.8, 4.3 Hz, 1H), 7.30- 7.16 (m, 1H),6.98 (t, J = 54.8 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.06 (t, J = 7.5Hz, 2H), 2.74 (s, 3H), 2.54 (s, 3H), 2.49 (t, J = 7.3 Hz, 2H), 1.54 (s,6H). 115 509.1  1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.43 (s, 1H),7.96 (s, 1H), 7.79 (q, J = 4.5 Hz, 1H), 7.75 (dd, J = 7.9, 2.0 Hz, 1H),7.46 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 55.9Hz, 1H), 4.14 (t, J = 7.2 Hz, 2H), 3.20 (td, J = 14.9, 11.8 Hz, 2H),3.01-2.84 (m, 4H), 2.59 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H), 2.37 (p, J =7.5 Hz, 2H). 116 527.1  1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.43(s, 1H), 7.99 (dd, J = 6.6, 2.6 Hz, 1H), 7.79 (q, J = 4.7 Hz, 2H),7.42-7.01 (m, 2H), 4.14 (t, J = 7.3 Hz, 2H), 3.20 (q, J = 14.6 Hz, 2H),2.92 (t, J = 7.7 Hz, 4H), 2.59 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H), 2.37(p, J = 7.4 Hz, 2H). 117 484.1  1H NMR (400 MHz, Acetone-d6) δ 9.05 (s,1H), 8.11-7.99 (m, 2H), 7.66 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.29 (t, J= 9.0 Hz, 1H), 4.49 (s, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.80 (s, 2H),3.13 (t, J = 7.5 Hz, 2H), 3.12-2.75 (m, 4H), 2.53 (s, 3H), 2.49 (p, J =7.4 Hz, 2H). 118 468.1  1H NMR (400 MHz, Acetone-d6) δ 9.07 (s, 1H),8.02 (s, 1H), 7.91 (ddd, J = 13.2, 7.4, 2.6 Hz, 1H), 7.50-7.41 (m, 1H),7.30 (dt, J = 10.5, 9.0 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.80 (d, J =1.1 Hz, 2H), 3.13 (t, J = 7.5 Hz, 2H), 3.10-2.76 (m, 4H), 2.53 (s, 3H),2.49 (p, J = 7.4 Hz, 2H). 119 499.24 1H NMR (400 MHz, Acetonitrile-d3) δ8.93 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.06(s, 1H), 7.94 (dd, J = 6.2, 2.1 Hz, 1H), 6.94 (s, 4H), 6.88 (t, J = 53.2Hz, 1H), 4.93 (dd, J = 12.1, 8.3 Hz, 2H), 4.81 (dd, J = 7.9, 3.9 Hz,2H), 4.31 (tt, J = 6.0, 1.8 Hz, 1H), 3.37 (dd, J = 18.8, 6.8 Hz, 1H),3.23-3.09 (m, 1H), 2.53 (s, 3H), 2.12 (dq, J = 8.0, 6.1 Hz, 1H), 1.09(dt, J = 8.6, 5.9 Hz, 1H), 0.33-0.21 (m, 1H). 120 497.2  1H NMR (400MHz, DMSO-d6) δ 9.98 (s, 1H), 9.39 (s, 1H), 7.94 (dd, J = 6.8, 2.6 Hz,1H), 7.58 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H),7.29 (s, 1H), 7.20 (s, 1H), 4.13 (t, J = 7.3 Hz, 2H), 3.20 (q, J = 14.2Hz, 2H), 2.93 (dt, J = 30.3, 7.1 Hz, 4H), 2.43 (s, 3H), 2.37 (t, J = 7.3Hz, 2H). 121 481.2  1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.39 (s,1H), 7.84-7.75 (m, 1H), 7.43-7.36 (m, 2H), 7.29 (s, 1H), 7.20 (s, 1H),4.13 (t, J = 7.2 Hz, 2H), 3.20 (q, J = 14.4 Hz, 2H), 2.93 (dt, J = 30.5,7.1 Hz, 4H), 2.43 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H). 124 524.9  1H NMR(400 MHz, Acetone-d6) δ 9.04 (s, 1H), 8.67 (s, 1H), 8.05 (dd, J = 6.8,2.6 Hz, 1H), 7.66 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.29 (t, J = 9.0 Hz,1H), 4.25 (t, J = 7.3 Hz, 2H), 3.53 (ddd, J = 15.3, 13.6, 11.9 Hz, 2H),3.22-3.00 (m, 7H), 2.91 (s, 3H), 2.53 (s, 3H), 2.49 (p, J = 7.4 Hz, 2H).125 509.0  1H NMR (400 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.88 (s, 1H),7.89 (ddd, J = 13.1, 7.4, 2.5 Hz, 1H), 7.45 (dq, J = 8.4, 2.0 Hz, 1H),7.29 (dt, J = 10.6, 9.1 Hz, 1H), 4.23 (t, J = 7.3 Hz, 2H), 3.63- 3.37(m, 2H), 3.18-2.97 (m, 7H), 2.90 (s, 3H), 2.51 (s, 3H), 2.50-2.43 (m,2H). 126 462.1  1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.39 (s, 1H),7.95-7.77 (m, 2H), 7.61-7.49 (m, 2H), 4.13 (t, J = 7.3 Hz, 2H), 2.86 (t,J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.37 (q, J = 7.5 Hz, 2H), 1.32- 1.23 (m,2H), 1.23-1.16 (m, 2H). 127 529.0  1H NMR (400 MHz, Methanol-d4) δ 7.76(ddd, J = 9.2, 8.2, 5.7 Hz, 1H), 7.24-7.03 (m, 1H), 4.24 (t, J = 7.3 Hz,2H), 3.30 (m, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.90 (td, J = 14.4, 6.7 Hz,2H), 2.82- 2.71 (m, 3H), 2.60 (s, 3H), 2.49 (p, J = 7.5 Hz, 2H). 128477.0  1H NMR (400 MHz, Methanol-d4) δ 7.86 (m, 1H), 7.50 (m, 1H), 7.21(m, 1H), 4.30-4.07 (m, 3H), 3.07-2.92 (m, 2H), 2.76 (m, 3H), 2.53 (s,3H), 2.51-2.40 (m, 2H), 2.11 (m, 1H), 0.98 (m, 6H). 129 528.9  1H NMR(400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.44 (s, 1H), 7.86-7.65 (m, 2H),4.13 (t, J = 7.3 Hz, 2H), 3.27-3.12 (m, 2H), 2.98-2.84 (m, 4H), 2.59 (d,J = 4.5 Hz, 3H), 2.43 (s, 3H), 2.37 (p, J = 7.6 Hz, 2H). 130 497.1  1HNMR (400 MHz, Acetone-d6) δ 9.09 (s, 1H), 8.99 (s, 1H), 8.05 (dd, J =6.8, 2.6 Hz, 1H), 7.66 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.30 (t, J = 9.0Hz, 1H), 4.27 (t, J = 7.3 Hz, 2H), 3.53 (tdt, J = 13.8, 8.5, 4.2 Hz,2H), 3.34 (qd, J = 12.2, 3.4 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H), 2.54 (s,3H), 2.50 (p, J = 7.4 Hz, 2H). 131 481.1  1H NMR (400 MHz, Acetone-d6) δ9.14 (s, 1H), 9.01 (s, 1H), 7.91 (ddd, J = 13.1, 7.4, 2.6 Hz, 1H),7.51-7.42 (m, 1H), 7.30 (dt, J = 10.6, 9.0 Hz, 1H), 4.27 (t, J = 7.3 Hz,2H), 3.63-3.45 (m, 2H), 3.34 (dt, J = 15.2, 12.3 Hz, 2H), 3.15 (t, J =7.5 Hz, 2H), 2.53 (s, 4H), 2.50 (p, J = 7.5 Hz, 1H). 132 490.1  1H NMR(400 MHz, Acetone-d6) δ 9.04 (s, 1H), 8.05 (dd, J = 6.8, 2.6 Hz, 1H),7.75 (s, 1H), 7.66 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.29 (t, J = 9.0 Hz,1H), 4.27 (t, J = 7.3 Hz, 2H), 4.15 (d, J = 11.8 Hz, 1H), 3.81 (dd, J =12.0, 1.7 Hz, 1H), 3.13 (t, J = 7.6 Hz, 2H), 2.54 (s, 3H), 2.49 (p, J =7.4 Hz, 2H), 1.66 (d, J = 1.0 Hz, 3H). 133 474.1  1H NMR (400 MHz,Acetone-d6) δ 9.06 (s, 1H), 7.91 (ddd, J = 13.1, 7.4, 2.6 Hz, 1H), 7.74(s, 1H), 7.46 (dddd, J = 9.0, 4.1, 2.6, 1.6 Hz, 1H), 7.30 (dt, J = 10.5,9.0 Hz, 1H), 4.76 (s, 1H), 4.31- 4.22 (m, 2H), 4.15 (d, J = 12.0 Hz,1H), 3.81 (d, J = 12.0 Hz, 1H), 3.13 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H),2.49 (p, J = 7.4 Hz, 2H), 1.66 (d, J = 1.0 Hz, 3H). 134 556.2  1H NMR(400 MHz, DMSO-d6) δ 10.15 (d, J = 1.6 Hz, 1H), 9.77 (s, 1H), 8.44 (d, J= 5.3 Hz, 1H), 8.21 (t, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.15 (t, J = 53.1Hz, 1H), 5.85-5.57 (m, 1H), 4.55- 4.40 (m, 2H), 3.37-3.25 (m, 4H), 3.22(dd, J = 18.8, 5.0 Hz, OH), 3.00 (dd, J = 26.6, 18.8 Hz, 1H), 2.52 (s,3H). 135 487.1  1H NMR (400 MHz, Acetone-d6) δ 9.07 (s, 1H), 8.32 (s,1H), 7.97-7.84 (m, 1H), 7.55-7.39 (m, 2H), 7.30 (qd, J = 9.0, 4.5 Hz,1H), 7.17 (s, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H),2.53 (s, 3H), 2.47 (p, J = 7.2 Hz, 2H), 2.01 (s, 3H). 136 487.1  1H NMR(400 MHz, Acetone-d6) δ 9.07 (s, 1H), 8.32 (s, 1H), 7.91 (dd, J = 13.1,7.7 Hz, 1H), 7.55-7.39 (m, 2H), 7.29 (d, J = 9.5 Hz, 1H), 7.17 (s, 1H),4.26 (t, J = 7.3 Hz, 2H), 3.22-3.06 (m, 2H), 2.53 (s, 3H), 2.47 (p, J =7.0, 6.6 Hz, 2H), 2.01 (s, 3H). 137 501.0  1H NMR (400 MHz, Acetone-d6)δ 9.13 (s, 1H), 8.35 (s, 1H), 7.91 (ddt, J = 12.8, 7.7, 2.3 Hz, 1H),7.73 (s, 1H), 7.53-7.42 (m, 1H), 7.37-7.20 (m, 1H), 4.26 (t, J = 7.4 Hz,2H), 3.12 (t, J = 7.7 Hz, 2H), 2.82 (d, J = 4.6, 3H), 2.53 (s, 3H), 2.47(p, J = 7.2 Hz, 2H), 1.95 (s, 3H). 138 501.0  1H NMR (400 MHz,Acetone-d6) δ 9.07 (s, 1H), 8.32 (s, 1H), 8.00-7.83 (m, 1H), 7.68 (s,1H), 7.55-7.37 (m, 1H), 7.37-7.21 (m, 1H), 4.26 (t, J = 7.4 Hz, 2H),3.12 (t, J = 7.6 Hz, 2H), 2.82 (d, J = 2.9 Hz, 3H), 2.53 (s, 3H), 2.47(p, J = 7.3 Hz, 2H), 1.95 (s, 3H). 140 499.1  1H NMR (400 MHz,Methanol-d4) δ 7.48 (dd, J = 10.0, 6.3 Hz, 2H), 4.22 (t, J = 7.5 Hz,2H), 3.41-3.34 (m, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.91 (td, J = 14.4,6.9 Hz, 1H), 2.54 (s, 3H), 2.50 (t, J = 7.5 Hz, 2H). 145 450.2 1H NMR(400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.15 (s, 0.6H), 9.02 (s, 0.4H),7.89-7.75 (m, 1H), 7.48-7.32 (m, 2H), 4.15 (m, 2H), 4.09 (m, 0.6H), 3.92(m, 1.4H), 3.52 (m, 1.4H), 3.19 (m, 0.6H), 2.97 (m, 2H), 2.44 (m, 5H),1.62 (s, 1H), 1.42 (s, 2H). 147 528.19 1H NMR (400 MHz, Chloroform-d) δ8.59 (t, J = 5.6 Hz, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.05 (s, 1H), 7.57(s, 1H), 6.64 (d, J = 15.8 Hz, 1H), 5.29 (s, 1H), 4.40 (t, J = 7.4 Hz,2H), 3.43 (td, J = 14.9, 11.0 Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H), 2.97-2.81 (m, 5H), 2.73 (s, 3H), 2.52 (p, J = 7.6 Hz, 2H). 150 523.2  1H NMR(400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.91 (s, 1H), 8.45 (d, J = 5.3 Hz,1H), 8.22 (t, J = 5.6 Hz, 1H), 7.16 (t, J = 53.1 Hz, 1H), 5.92- 5.62 (m,1H), 4.87 (dd, J = 12.2, 8.4 Hz, 2H), 4.77 (dd, J = 7.9, 2.4 Hz, 2H),4.56-4.42 (m, 2H), 3.45 (ddd, J = 37.2, 18.9, 5.0 Hz, 1H), 3.22 (dd, J =26.5, 18.9 Hz, 1H), 2.54 (s, 3H). 151 450.2  1H NMR (400 MHz, DMSO-d6) δ10.03 (s, 1H), 9.03 (s, 1H), 7.82 (ddd, J = 14.3, 7.8, 2.2 Hz, 1H),7.49-7.34 (m, 2H), 4.21-4.04 (m, 4H), 3.23-3.15 (m, 2H), 2.96 (t, J =7.5 Hz, 2H), 2.47-2.39 (m, 5H), 1.62 (s, 3H). 152 450.2  1H NMR (400MHz, DMSO-d6) δ 10.14 (s, 1H), 9.51 (s, 1H), 7.93-7.74 (m, 1H),7.51-7.34 (m, 2H), 7.30 (s, 1H), 7.26 (s, 1H), 4.84 (dd, J = 25.0, 6.6Hz, 2H), 4.62 (dd, J = 31.2, 6.6 Hz, 2H), 4.24 (t, J = 6.0 Hz, 1H),3.30-3.20 (m, 1H), 3.10 (d, J = 18.7 Hz, 1H), 2.42 (s, 3H), 2.11 (t, J =7.0 Hz, 1H), 1.07 (dt, J = 8.4, 5.7 Hz, 1H), 0.15 (q, J = 3.6, 1.9 Hz,1H).

BIOLOGICAL EXAMPLES HBV DNA Quantification Assay

A HepG2 cell line overexpressing the HBV virus attachment receptorsodium-taurocholate cotransporting polypeptide (NTCP) was grown toconfluency in DMEM growth medium, Dulbecco's Modified Eagle Mediumwithout sodium pyruvate (Life Technologies, Rockville, Md.) supplementedwith 10% FBS (Thermo Scientific, Waltham, Md.), 1%penicillin/streptomycin (Life Technologies, Rockville, Md.) and 2 mML-glutamine (Life Technologies, Rockville, Md.) in T175 flasks. Cellswere infected with HBV AD38 viral particles (Texcell, Frederick, USA) at4000 genome equivalents per cell. After allowing viral infection to takeplace for 4 days, the infected cells were harvested from the flasks bytrypsinization, washed twice with OptiMEM (Life Technologies, Rockville,Md.) and re-suspended in DMEM containing 2% FBS and 1% DMSO at a densityof 0.25E6 cells/ml. Infected cells were seeded on 384 well collagencoated plates (Greiner, Austria) at a density of 20,000 cells/wellcontaining serially diluted compounds of the present disclosure or DMSO(0.5%) in a final volume of 80 μl. The assay plates were incubated for aperiod of 5 days and the antiviral activity of the test compounds wereassayed by detecting the presence of HBV DNA in the culture supernatantusing the QuantiGene™ 2.0 nucleic acid quantification kit (Affymetrix,Santa Clara, Calif.).

The culture supernatant was harvested and treated with lysis buffercontaining Proteinase K (Affymetrix, Santa Clara, Calif.). Thesupernatant was incubated with HBV viral DNA specific probes(Affymetrix, Santa Clara, Calif.) for 30 minutes at 55° C. This wasfollowed by addition of 0.2M NaOH for 30 minutes at room temperature todenature the DNA, followed by addition of Neutralization buffer(Affymetrix, Santa Clara, Calif.). The resulting lysed and neutralizedsupernatant was then added to QuantiGene™ 2.0 384 well plates coatedwith capture oligonucleotides and incubated overnight at 55° C. The HBVspecific probe set consists of Capture Extender oligonucleotides (CE's)and blocking probes. Following the overnight incubation, the wells wereincubated for one hour sequentially with a Pre-Amplifier, Amplifier andLabeled probes conjugated to alkaline phosphatase with a wash stepbetween incubations. After the final wash step, the alkaline phosphatasesubstrate (Luminol APS5) was added and the resulting luminescence signalwas read in an EnVision Multilabel Plate Reader (PerkinElmer, SantaClara, Calif.). The EC50 values were calculated from the fit of thedose-response curves to a four-parameter equation. All EC50 valuesrepresent geometric mean values of a minimum of four determinations.EC50 values for certain compounds of the present disclosure are reportedin the table below.

EC50-NTCP Compound (nM) 1 27.1 2 15.9 3 14.9 4 63.6 5 8.8 6 11.1 7 5.8 872.0 9 103.4 10 56.1 11 7.7 12 5.0 13 252.3 14 8.8 15 45.8 16 456.1 1764.5 18 33.2 19 167.3 20 49.4 21 20.1 22 37.0 23 66.0 24 43.7 25 407.926 14.6 27 32.3 28 112.0 29 3.1 30 58.1 31 3.2 32 8.5 33 27.2 34 202.235 109.1 36 24.0 37 5.6 38 13.0 39 2.1 40 1.9 41 7.5 42 2.1 43 23.2 4431.0 45 9.1 46 263.8 47 56.3 48 6.5 49 69.1 50 53.7 51 75.9 52 7.7 533.2 54 7.8 55 54.3 56 87.1 57 9.9 58 27.3 59 23.8 60 1.8 61 12.3 62 78.663 71.1 64 30.1 65 36.8 66 6.5 67 6.5 68 110.4 69 49.9 70 63.2 71 15.472 69.8 73 15.8 74 42.0 75 106.5 76 31.9 77 19.0 78 16.4 79 47.8 80 8.781 17.5 82 133.3 83 198.9 84 31.0 85 293.6 86 184.0 87 12.5 88 8.7 892.9 90 182.6 91 91.1 92 6.4 93 253.9 94 5.8 95 33.7 96 16.5 98 30.6 9951.3 100 3.7 101 29.8 102 111.9 103 40.8 104 96.4 105 170.2 106 123.9107 145.9 111 153.7 112 29.9 113 45.1 114 156.5 115 49.9 116 24.2 11713.1 118 26.1 119 25.8 120 12.3 121 14.4 124 11.9 125 23.1 126 165.8 12732.3 128 169.9 129 20.4 130 10.4 131 10.6 132 8.3 133 16.5 134 23.8 13579.9 136 70.1 137 158.2 138 159.8 140 12.2 145 46.3 147 102.7 150 74.3151 30.6 152 65.1

Hepatic Stability Assay

The metabolic stability of certain compounds disclosed herein wasassessed in vitro in pooled cryopreserved hepatocytes using the in vitrohalf-life method. Incubations were at 37° C. and final concentrations inthe incubations were 1×10⁶ cells/mL and 1 mM test concentration of thecompound. Aliquots were sequentially removed after 0, 1, 3 and 6 hoursand analyzed by LC-MS/MS. In vitro half-life was determined by measuringthe rate of disappearance of the compound and then scaled to predictedhepatic clearance using the well-stirred model. Data is presented in thetable below. This data may be used to compare the relative metabolicstabilities of the compounds. For reference, 39.5 hours is the maximumdetectable half life for this assay. As such, compounds having a valueof 39.5 may have a half live that exceeds 39.5 hours.

Compound t½ (hours) 1 2 15 3 35.1 4 7.3 5 5.2 6 8.2 7 4.8 8 0.4 9 11.710 1 11 0.7 12 6.4 13 16.4 14 2.1 15 0.5 16 11.8 17 0.6 18 6 19 18.3 2014.3 21 17.1 22 2.7 23 9.6 24 5 25 9.1 26 8.2 27 0.9 28 11.8 29 16.1 3027.2 31 8.6 32 8.8 33 4.3 34 18.1 35 39.5 36 26.5 37 10.9 38 13.8 39 4.240 5.2 41 4.9 42 3.5 43 16 44 39.5 45 13.3 46 16 47 39.5 48 7.9 49 39.550 15.3 51 9.5 52 4.2 53 10.8 54 6.7 55 15.5 56 39.5 57 8.0 58 38.5 5922.3 60 3.9 61 5.4 62 5.3 63 11.2 64 13.2 65 14.8 66 1.4 67 68 5.2 6917.0 70 39.5 71 7.3 72 39.5 73 16.1 74 22.2 75 17.3 76 19.5 77 22.1 784.8 79 14.9 80 6.3 81 8.0 82 83 19.2 84 10.7 85 86 9.4 87 6.3 88 9.9 8910.3 90 31.4 91 19.6 92 2.2 93 29.9 94 2.9 95 28.8 96 22.6 98 14.8 999.6 100 3.1 101 7.0 102 4.8 103 8.5 104 105 24.3 106 107 9.8 111 10.1112 113 114 115 39.5 116 39.5 117 10.5 118 15.2 119 11.0 120 13.5 12119.8 124 1.0 125 1.9 126 10.7 127 15.2 128 129 20.8 130 6.60 131 7.60132 7.70 133 12.5 134 17.9 135 39.5 136 39.5 137 7.4 138 17.9 140 13.5145 9.7 147 24.8 150 16.6 151 5.0 152 10.5

1. A compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁₋₆ alkyloptionally substituted with 1 to 3 R^(1A), C₃₋₈ cycloalkyl optionallysubstituted with 1 to 4 R^(1B), or 3 to 8 membered monocyclic orbicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, andS, optionally substituted with 1 to 3 R^(1C); each R^(1A) isindependently halogen, —OH, —CN, C₁₋₂ haloalkyl, —C(O)NR^(X)R^(Y), C₆₋₁₀aryl optionally substituted with 1 to 3 R^(1D), or a 5 to 8 memberedheteroaryl having 1 to 3 heteroatoms selected from N, O, and S,optionally substituted with 1 to 3 R^(1D), provided no more than 1R^(1A) is C₆₋₁₀ aryl optionally substituted with 1 to 3 R^(1D) or 5 to 8membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;each R^(1B) is independently —CN, halogen, C₁₋₆ alkyl optionallysubstituted with 1 to 3 —OH or —NR^(a)R^(b), C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl, —C(O)NR^(X)R^(Y), or a 5 to 8 memberedheteroaryl having 1 to 3 heteroatoms selected from N, O, and Soptionally substituted with 1 to 3 R^(1D), provided no more than 1R^(1B) is C₃₋₆ cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S; each R^(1C) is independently C₁₋₆alkyl, oxo, C₁₋₄ haloalkyl, —C(O)H, —C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl,or a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected fromN, O, and S optionally substituted with 1 to 3 R^(1D) provided no morethan 1 R^(1C) is a 5 to 12 membered heteroaryl having 1 to 3 heteroatomsselected from N, O, and S; each R^(X) is independently —H, C₃₋₆cycloalkyl, C₁₋₆ alkyl optionally substituted with 1 to 3 R^(Z), 3 to 8membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S, optionally substituted with 1 to 3 R^(Z);each R^(Y) is independently —H or C₁₋₆ alkyl optionally substituted with1 to 3 R^(Z); or R^(X) and R^(Y) are taken together to form a 3 to 8membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S, optionally substituted with 1 to 3 R^(Z);wherein each R^(Z) is independently halogen, methyl, ethyl, oxo, —OH,—S(O)₂C₁₋₃alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclylhaving 1 to 3 heteroatoms selected from N, O, and S; each R^(a) is —H,C₁₋₃alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclylhaving 1 to 3 heteroatoms selected from N, O, and S, optionallysubstituted with 1 to 3 R^(Z); each R^(b) is —H or C₁₋₃alkyl; or R^(a)and R^(b) taken together form a 3 to 8 membered monocyclic or bicyclicheterocycle optionally substituted with 1 to 3 R^(Z); the moiety

 is a pyrrolidine or a 5-7 membered bicyclic heterocycle having onenitrogen, optionally substituted with 1 to 6 R² groups; wherein each R²is independently halogen, C₁₋₃alkyl, —OH, or —OC₁₋₃ alkyl; R³ is —H,halogen, or C₁₋₄ alkyl; R⁴ is phenyl optionally substituted with 1 to 5R^(4A), or pyridinyl optionally substituted with 1 to 4 R^(4B); and eachR^(1D), R^(4A), and R^(4B) are independently —CN, halogen, C₁₋₄ alkyl,—OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.
 2. (canceled)
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is phenyl optionally substituted with 1 to 3 R^(4A).
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(4A) is independently Cl, F, —CF₃, —CHF₂, —CH₃, —OCF₃,—OCF₂H, or —CN.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is —Cl or —CH₃.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is—CH₃.
 7. (canceled)
 8. (canceled)
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is acompound of Formula (II)

wherein: R¹ is C₁₋₆ alkyl optionally substituted with 1 to 3 R^(1A),C₃₋₈ cycloalkyl optionally substituted with 1 to 4 R^(1B), or 3 to 8membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatomsselected from N, O, and S, optionally substituted with 1 to 3 R^(1C);each R^(1A) is independently halogen, —OH, —CN, C₁₋₂ haloalkyl,—C(O)NR^(X)R^(Y), C₆₋₁₀ aryl optionally substituted with 1 to 3 R^(1D)or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected fromN, O, and S, optionally substituted with 1 to 3 R^(1D), provided no morethan 1 R^(1A) is C₆₋₁₀ aryl optionally substituted with 1 to 3 R^(1D) or5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O,and S; each R^(1B) is independently halogen, C₁₋₆ alkyl optionallysubstituted with 1 to 3 —OH or —NR^(a)R^(b), C₁₋₄ alkoxy, C₁₋₂haloalkyl, —C(O)NR^(X)R^(Y), or 5 to 8 membered heteroaryl having 1 to 3heteroatoms selected from N, O, and S optionally substituted with 1 to 3R^(1D), provided no more than 1 R^(1B) is 5 to 8 membered heteroarylhaving 1 to 3 heteroatoms selected from N, O; each R^(1C) isindependently C₁₋₆ alkyl, oxo, C₁₋₄ haloalkyl, —C(O)H, —C(O)C₁₋₄ alkylor —C(O)OC₁₋₄ alkyl; each R^(X) is independently —H, C₃₋₆ cycloalkyl,C₁₋₆ alkyl optionally substituted with 1 to 3 R^(Z), 3 to 8 memberedmonocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selectedfrom N, O, and S, optionally substituted with 1 to 3 R^(Z); each R^(Y)is independently —H or C₁₋₆ alkyl optionally substituted with 1 to 3R^(Z); or R^(X) and R^(Y) are taken together to form a 3 to 8 memberedmonocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selectedfrom N, O, and S, optionally substituted with 1 to 3 R^(Z); wherein eachR^(Z) is independently halogen, methyl, ethyl, oxo, —OH,—S(O)₂C₁₋₃alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclylhaving 1 to 3 heteroatoms selected from N, O, and S; each R^(a) is —H,C₁₋₃alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclylhaving 1 to 3 heteroatoms selected from N, O, and S, optionallysubstituted with 1 to 3 R^(Z); each R^(b) is —H or C₁₋₃alkyl; or R^(a)and R^(b) taken together form a 3 to 8 membered monocyclic or bicyclicheterocyclyl optionally substituted with 1 to 3 R^(Z); each of R^(2A),R^(2B), R^(2C), R^(2D), R^(2E), and R^(2F) are independently —H,halogen, C₁₋₃alkyl, —OH, or —OC₁₋₃ alkyl, or R^(2C) or R^(2D) may betaken together with R^(2E) or R^(2F) to form a cyclopropyl group; R³ ishalogen or methyl; R⁴ is phenyl optionally substituted with 1 to 5R^(4A), or pyridinyl, optionally substituted with 1 to 4 R^(4B); andeach R^(1D), R^(4A), and R^(4B) are independently —CN, halogen, C₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄ haloalkyl, or C₁₋₄ haloalkyl.
 10. (canceled)11. (canceled)
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is a compound of Formula(IV):

13-16. (canceled)
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is


18. (canceled)
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

20.-32. (canceled)
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

34.-36. (canceled)
 37. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

38.-41. (canceled)
 42. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is


43. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein wherein R¹ is.


44. (canceled)
 45. (canceled)
 46. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is pyridinyl,optionally substituted with 1 to 4 R^(4B).
 47. The compound of claim 46,wherein R⁴ is pyridin-4-yl, optionally substituted with 1 to 3 groupsselected from F, Cl, CF₃, and CHF₂.
 48. The compound of claim 1, or apharmaceutically acceptable salt thereof, which is


49. The compound of claim 1, or a pharmaceutically acceptable saltthereof, which is


50. The compound of claim 1, or a pharmaceutically acceptable saltthereof, which is


51. The compound of claim 1, which is

or a pharmaceutically acceptable salt thereof.
 52. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof. 53.-57. (canceled)
 58. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. 59.-62. (canceled)
 63. A method of treating orpreventing a HBV infection, comprising administering to an individual inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof. 64.-75. (canceled) 76.A compound having the structure: